Obesity-associated Breast Cancer:

Analysis of risk factors 25

Atilla Engin

Abstract

Several studies show that a significantly stronger association is obvious

between increased body mass index (BMI) and higher breast cancer inci-
dence. Furthermore, obese women are at higher risk of all-cause and breast
cancer specific mortality when compared to non-obese women with breast
cancer. In this context, increased levels of estrogens due to excessive aroma-
tization activity of the adipose tissue, overexpression of pro-­inflammatory
cytokines, insulin resistance, hyperactivation of insulin-like growth factors
(IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and
excessive oxidative stress contribute to the development of breast cancer in
obese women. While higher breast cancer risk with hormone replacement
therapy is particularly evident among lean women, in postmenopausal
women who are not taking exogenous hormones, general obesity is a signifi-
cant predictor for breast cancer. Moreover, increased plasma cholesterol
leads to accelerated tumor formation and exacerbates their aggressiveness.
In contrast to postmenopausal women, premenopausal women with high
BMI are inversely associated with breast cancer risk. Nevertheless, life-style
of women for breast cancer risk is regulated by avoiding the overweight and
a high-fat diet. Estrogen-plus-progestin hormone therapy users for more
than 5 years have elevated risks of both invasive ductal and lobular breast
cancer. Additionally, these cases are more commonly node-positive and
have a higher cancer-related mortality. Collectively, in this chapter, the
impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin
and adiponectin concentrations, aromatase activity, leptin and insulin resis-
tance on breast cancer patients are evaluated. Obesity-related prognostic
factors of breast cancer also are discussed at molecular basis.

A. Engin, M.D., Ph.D. (*)

Faculty of Medicine, Department of General Surgery,
Gazi University, Besevler, Ankara, Turkey
Mustafa Kemal Mah. 2137. Sok. 8/14, 06520,
Cankaya, Ankara, Turkey
e-mail: dr.aengin@gmail.com

© Springer International Publishing AG 2017 571

A.B. Engin, A. Engin (eds.), Obesity and Lipotoxicity, Advances in Experimental
Medicine and Biology 960, DOI 10.1007/978-3-319-48382-5_25
572 A. Engin

Keywords
Breast cancer • Obesity • Fatty acid • Postmenopausal breast cancer •
Premenopausal breast cancer • Estrogen • Leptin • Adiponectin • Aromatase
• Insulin resistance • Mammalian target of rapamycin (mTOR) • Insulin-
like growth factor (IGF) • Human epidermal growth factor receptor 2
(HER2) • Estrogen receptor (ER) • Progesteron receptor (PR) • Cyclin D1
• Liver X receptor (LXR) • Oxysterol 27-hydroxycholesterol (27HC) •
Sex hormone-binding globulin (SHBG) • Estrone • Hypoxia •
Hyperinsulinemia • Aryl hydrocarbon receptor (AHR) • Breast cancer
recurrence • Cancer-associated adipocytes (CAAs) • Leptin resistance

and breast cancer specific mortality when com-

1 Introduction pared to non-obese women with breast cancer
(Demark-Wahnefried et al. 2012). In this respect,
High body mass index (BMI) is associated with overweight women should avoid weight gain
increased risk of some cancer types. In 1402 of during treatment and obese women should lose
108,812 individuals from the general population weight immediately after treatment (Rock et al.
developed breast cancer during a median of 4.7-­ 2012). Of 53,816 women treated for early-stage
years follow-up. In this series of patients, corre- breast cancer, 18,967 patients with complete fol-
sponding risk of breast cancer was 20% higher in low-­up have been evaluated up to 10 years and
postmenopausal women with high BMI (Benn up to 30 years for the loco-regional recurrences
et al. 2016). However, a significantly stronger or distant metastases and for death, respectively.
association between increased BMI and higher The risk of developing distant metastases after 10
breast cancer incidence is observed in the Asia-­ years was significantly increased which was by
Pacific group than in European-Australian or 46%, and the risk of dying as a result of breast
North-American group (Wang et al. 2016). In the cancer after 30 years was significantly increased
Asia-Pacific region, every additional 5 kg/m2 which was by 38% for patients with a BMI of 30
increase in BMI corresponds to a 31% increase in kg/m2 or more. However, BMI had no influence
postmenopausal breast cancer risk (Renehan on the risk of loco-regional recurrences (Ewertz
et al. 2008). Although overweight is related to a et al. 2011). Indeed, high BMI is associated with
higher risk of mortality, the number of obese worse long-term outcomes among obese women,
female breast cancer survivors is growing as a who have breast cancer (Kamineni et al. 2013).
consequence of advances in treatment strategies In addition, increase in post-diagnostic body
and early diagnosis. In this respect, the number of weight is common in women with breast cancer.
breast cancer survivors is increasing by approxi- In this respect, particularly chemotherapy treat-
mately 3% each year (Maddams et al. 2009). ment has been considered as a significant con-
Evaluation of 79 publications from 82 follow-up tributory ­ factor through reduced metabolism
studies clearly indicate that, amongst the breast (Demark-­ Wahnefried et al. 2012). Inter-linked
cancer survivors, higher BMI is consistently molecular mechanisms between obesity and
associated with lower overall and breast cancer breast cancer might be involved in the pathogen-
survival. Analysis of 23,182 deaths of 213,075 esis in postmenopausal women. In this context,
breast cancer survivors confirmed that the current increased levels of estrogens due to excessive
guideline for breast cancer survivors is to remain aromatization activity of the adipose tissue,
as lean as possible within the normal range of ­overexpression of inflammatory cytokines, insu-
body weight (Chan et al. 2014). Another meta-­ lin resistance, hyperactivation of insulin-like
analysis includes results from 43 studies show growth factors (IGFs) pathways, adipocyte-
that obese women are at higher risk of all-cause derived adipokines, and excessive oxidative
25 Obesity-associated Breast Cancer: Analysis of risk factors
stress contribute to the development of breast
cancer in obese women. These factors also
­interfere with intracellular signaling in the mito-
gen-activated protein kinase (MAPK) and phos-
phatydilinositol-3-phosphate (PI3P)/mammalian
target of rapamycin (mTOR) pathway (Simone
et al. 2016).
The interaction between human-derived adi-
pocytes and primary breast cancer cells increase
the secretion of pro-inflammatory cytokines.
Furthermore, contact with immature adipocytes
increase the abundance of cancer cells with
tumor-forming and metastatic potential in vivo
(Picon-Ruiz et al. 2016). The expression level of
the fat mass-obesity associated genes in breast
cancer tissues is significantly higher than that in
the adjacent healthy breast tissues. However,
there is no correlation between fat mass-obesity
associated gene expression and age, tumor stage,
lymph node status, TNM stage, Ki67, and BMI in
breast cancer. Despite all these, fat mass-obesity
associated gene expression has very important
role in human epidermal growth factor receptor 2
(HER2)-overexpressed breast cancer (Tan et al.
2015). In the women undergoing mastectomy for
breast cancer risk reduction or for breast cancer
treatment, white adipose tissue inflammation in
breast specimens is detected in 52% and 41% of
patients, respectively. In these patients, white
adipose tissue inflammation is defined by the
presence of dead adipocytes surrounded by mac-
rophages forming crown-like structures in the
breast adipose tissue (Iyengar et al. 2016).
During the 4.7 years-follow-up of 73,542 pre-
menopausal and 103,344 postmenopausal women
from nine European countries, 1879 incidental
invasive breast cancers have been diagnosed.
While excess breast cancer risk with hormone
replacement therapy is particularly evident
among lean women, in postmenopausal women
who are not taking exogenous hormones, general
obesity is a significant predictor of breast cancer.
In contrast to postmenopausal women, among
premenopausal women, high BMI is inversely,
but not significantly, associated with breast can-
cer risk. This meta-analysis indicates a 2% reduc-
tion in risk per unit of increase in BMI (1 kg/m2)
among premenopausal women, whereas a 3%
573
increase in risk of breast cancer among post-
menopausal non-hormone replacement therapy
users (Lahmann et al. 2004). Considering the
relationship between breast cancer and obesity;
the postulated mechanisms for the increased risk
of breast cancer in obese women, such as elevated
estrogen levels, insulin resistance and the influ-
ences of IGF, fatty acids, leptin and adiponectin
will be discussed in this chapter.
2  strogens as a Cause
E
of Breast Cancer in Obesity
There is abundance of data linking obesity-­
related breast cancer to estrogen receptor signal-
ing. As comorbidities of obesity; excessive local
production of estrogens in adipose tissue, the
influence of adipokines and inflammatory cyto-
kines, finally hypercholesterolemia have also
been established as independent risk factors for
breast cancer in postmenopausal women (Boyd
and McGuire 1990; McDonnell et al. 2014a).
Despite accumulated observational evidences,
risks and benefits of estrogen use are evaluated
with the increase in absolute excess risk for
occurrence of invasive breast cancers. On May
31, 2002, after a mean of 5.2 years of follow-up,
the data and safety monitoring board recom-
mended stopping the trial of estrogen-plus-­
progestin versus placebo, because the test
statistic for invasive breast cancer exceeded the
average incidence of this adverse effect (Rossouw
et al. 2002). Over an average follow-up of 6.8
years, the use of 0.625 mg/day of conjugated
equine estrogen increases the risk of stroke,
decreases the risk of hip fracture, and does not
affect coronary heart disease incidence in post-
menopausal women with prior hysterectomy.
Finally, in February 2004, the National Institutes
of Health decided to end the intervention phase
of the trial early by taking into consideration of
these data (Anderson et al. 2004). In a total of
16,608 women without hysterectomy and ran-
domized to the estrogen-plus-progestin trial, the
higher breast cancer risk seen during intervention
that is followed by a substantial drop in the risk
of the early post-intervention phase, but the
574
higher breast cancer risk remains during the late
post-­intervention phase of follow-up period. The
10,739 women with prior hysterectomy are ran-
domized according to the estrogen alone trial.
Despite the lower breast cancer risk that is
observed during the early post-intervention
phase, during the late post-intervention period a
higher breast cancer risk is determined
(Chlebowski et al. 2015). Collectively, the results
of these data indicate that in estrogen-plus-­
progestin group, breast cancer incidence is
higher, and the cases are more commonly node-
positive. Breast cancer mortality also appears to
be increased with combined use of estrogen-plus-­
progestin (Chlebowski et al. 2010). Breast cancer
incidence rate decreases with body mass among
premenopausal women in high-risk countries,
but this ratio rises with the increase in body mass
in all other groups of women (Pathak and
Whittemore 1992). More detailed analysis
revealed that decreased risk of breast cancer
associates with increased body size among pre-
menopausal women, however this event is lim-
ited to the youngest age group only (Peacock
et al. 1999). Furthermore, obesity may influence
the levels of endogenous sex-steroid and IGF-­
related hormones in the circulation, especially
after menopause. In the post-menopausal group,
increases in estrogens, testosterone and andro-
stenedione are correlated with increasing BMI. In
contrast, sex hormone-binding globulin decreases
with increasing BMI (Lukanova et al. 2004;
McTiernan et al. 2006). Obese women have 35%
higher concentrations of estrone and 130% higher
concentrations of estradiol compared with
normal-­weight women. Testosterone concentra-
tions also increase with increasing levels of adi-
posity. Concentrations of free estradiol and free
testosterone are two to three times greater in
overweight and obese women compared with
normal-weight women (McTiernan et al. 2003).
Obese never users of hormone therapy have 1.7-
to 2.3-fold elevated risks of ductal and estrogen
receptor (ER) positive-progesteron receptor (pos-
itive-­
PR) positive breast cancer, respectively,
compared to thinner women. Estrogen-plus-­
progestin hormone therapy users for more than 5
years have 2.1 to 9.6-fold elevated risks of lobu-
A. Engin
lar and ER positive-PR positive tumors compared
to never users of hormone therapy regardless of
BMI. Current estrogen-plus-progestin hormone
therapy users for more than 5 years with a BMI
less than 24.9 kg/m2 also have a 2.6-fold elevated
risk of ductal breast cancer (Li et al. 2006). In
eleven original articles, the case-case comparison
showed a significant association between triple
negative breast cancer and obesity. When the
patients are stratified based on menopausal sta-
tus, significant results are observed only in the
premenopausal group and triple negative tumors
with ER negative-PR negative/HER2-found to
have positive associations with obesity but only
among premenopausal women (Pierobon and
Frankenfeld 2013). In a prospective cohort of
67,754 postmenopausal women, 1821 cases of
invasive ductal breast cancer and 471 cases of
invasive lobular or mixed lobular cancer occurred
during 13 years of follow-up. Use of exogenous
estrogen plus progesterone is associated with an
increased risk of both ductal and lobular breast
cancer. Risk increased within the first 2–3 years
of use and attenuated 2 years after cessation. In
contrast, use of estrogen-only is not associated
with an overall increased risk of invasive ductal
cancer. Estrogen-only use is associated with a
50% increased risk of invasive lobular cancer
after more than 10 years of use (Calle et al. 2009).
In this case, estrogens are converted to metabo-
lites, particularly the catechol estrogen-3,4-­
quinones (CE-3,4-Q), that can react with DNA to
form depurinating adducts. These adducts are
released from DNA to generate apurinic sites.
Depurinating adducts 4-hydroxyestrone (estra-
diol), 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-
1-N7Gua constitute more than 99% of the total
DNA adducts formed. Increased levels of these
quinones and their reaction with DNA occur
when estrogen metabolism is unbalanced
(Cavalieri et al. 2006). Risk for ER negative-PR
negative tumors among postmenopausal women
slightly increases, but this is significantly differ-
ent from risk for ER positive-PR positive tumors.
The association between adult weight gain and
postmenopausal breast cancer risk is heteroge-
neous according to ER/PR status and stronger for
25 Obesity-associated Breast Cancer: Analysis of risk factors
ER positive-PR positive than for ER negative-PR
negative tumors (Vrieling et al. 2010).
3  holesterol and Breast
C in hypercholesterolemic animals (Alikhani et al.
Cancer in Obesity
In association with oncogenic stimuli, increased
plasma cholesterol leads to accelerated tumor
formation and increases tumor burden. In mam-
mary tumors increased plasma cholesterol levels
are associated with increased expression of cyclin
D1, a marker associated with tumor formation,
and decreased expression of markers associated
with protection. Both high density lipoproteins
and scavenger receptor type BI proteins are ele-
vated in animals that are fed a cholesterol-rich
diet. An increase in plasma cholesterol levels
accelerates the development of tumors and exac-
erbates their aggressiveness (Llaverias et al.
2011). The increased availability of high density
lipoproteins may increase the estradiol access to
the cancer tissue. While lipoproteins may regu-
late endothelial function in the tumor, they may
also affect the transport of estrogen. In addition,
scavenger receptor type BI may promote estra-
diol uptake (Brodeur et al. 2008). The binding of
high density lipoprotein (HDL) to scavenger
receptor type BI activates Ras in a protein kinase
C (PKC)-independent manner with subsequent
induction of the MAPK signaling cascade
(Grewal et al. 2003). Many metabolic pathways,
which have critical roles in progression of breast
cancer may induce MAPK signaling cascade. In
this respect, fatty acid binding protein 4 (FABP4)
enhances the proliferation of breast cancer cells
by inducing the Akt and MAPK signaling cas-
cades (Guaita-Esteruelas et al. 2016). Adiponectin
receptor 1 (AdipoR1), adaptor protein APPL1,
ER-alpha, Insulin like growth factor 1 receptor
(IGF-R1), and c-Src that is also responsible for
MAPK signaling activation in ER-delta positive
breast cancer cells (Mauro et al. 2014).
Furthermore, circulating factors in the serum of
obese postmenopausal women stimulate
ER-alpha positive breast cancer cell viability and
growth by facilitating non-genomic ER-alpha
crosstalk with the PI3K/Akt and MAPK signal-
575
ing pathways (Bowers et al. 2013). Indeed,
increased phosphatidylinositol 3-kinase (PI3K)
activity and Akt phosphorylation is a favorable
setting for mammary tumor growth and metastasis
2013) (Fig. 25.1).
Actually, the oxysterol 27-hydroxycholesterol
(27HC) is synthesized from cholesterol by
CYP27A1 which is a rate limiting enzyme. Hence
in humans, the circulating levels of 27HC closely
reflects those of cholesterol and hypercholesterol-
emia (Karuna et al. 2011) 27HC is a liver X recep-
tor (LXR) agonist and as such serves to limit
cholesterol accumulation in cells (Fu et al. 2001)
LXRs, as antiproliferative factors suppress growth
of both normal and breast cancer cells (Vigushin
et al. 2004). Interestingly, LXRs might have a
dual role in this respect. On the one hand, LXRs
are antiproliferative in the breast cancer cells. On
the other hand, LXR-induced expression of lipo-
genic genes peaked at lower 27HC concentration
are needed for the antiproliferative effect of LXR
(Vedin et al. 2009). Nevertheless, genetic or phar-
macological activation of LXR results in estro-
gen deactivation, which in turn inhibits breast
cancer growth (Gong et al. 2007). In contrast,
27HC is an estrogen receptor agonist in breast
cancer cells and it stimulates the growth and
metastasis of tumors in breast cancer of obese
women (McDonnell et al. 2014b). In human
breast cancer specimens, tumor grade is corre-
lated with CYP27A1 expression levels. In high-
grade tumors, both tumor cells and
tumor-associated macrophages display high
expression levels of this enzyme. Thus, 27HC
actually promotes the proliferation of ER-positive,
but not ER-negative breast cancer cell lines
(Nelson et al. 2013). In ER-positive breast cancer
patients, 27HC content in normal breast tissue is
increased compared to the cancer-­free controls,
and the tumor 27HC abundance is further ele-
vated. Cancer 27HC content is not influenced by
circulating levels of 27HC or its precursors.
Increases in tumor 27HC are directly related to
diminished expression of the 27HC metabolizing
enzyme CYP7B1. Actually, 27HC is a locally-
modulated, non-aromatized ER ligand that pro-
motes ER positive breast cancer growth (Wu et al.
576
Fig. 25.1 The postulated mechanisms for the increased
risk of breast cancer in obese women; elevated estrogen
levels, insulin resistance and the influences of IGF, fatty
acids, leptin and adiponectin (ROS reactive oxygen radi-
cals, PI3K phosphatidylinositol 3-kinase, MAPK mitogen-­
activated protein-kinase, Akt protein kinase B, FFA free
fatty acid, SHBG sex hormone-binding globulin, TNF-­
alpha tumor necrosis factor-alpha, IL-6 interleukin-6,
NF-kappaB nuclear factor-kappaB, IKK inhibitor kappa B
kinase, mTOR mammalian target of rapamycin, VEGF
vascular endothelial growth factor, PAI-1 plasminogen
activator inhibitor-1, IGF-1 insulin-like growth factor-1,
2013). Interestingly, tumor infiltration by macro-
phages is associated with their ability to produce
27HC within tumors and induce ER-alpha activity
(McDonnell et al. 2014a) (Fig. 25.1).
4 Obesity-Related Aromatase
Activity in Breast Cancer
While the ovaries are the primary source of estro-
gens in premenopausal women, estrogen synthe-
sis also occurs in the adipose tissue. Estrogens
A. Engin
IGFBP insulin-like growth factor binding protein, CYP19
aromatase cytochrome P450, product of the CYP19 gene,
CYP1B1 cytochrome P-450 1B1, CYP1A1 cytochrome
P-450 1A1, 2-OHE2 2-hydroxy estradiol, 4-OHE2
4-hydroxyestradiol, ER-alpha estrogen receptor-alpha,
ER-beta estrogen receptor-beta, STAT3 signal transducers
and activators of transcription-3, ERK extracellular signal-­
regulated kinase, AP-1 activating protein-1, MAPK
mitogen-­activated protein-kinase, TLR4 Toll like recep-
tor-­4, COX-2 cyclooxygenase-2, LXR liver X receptor,
Adipo R1/R2 adiponectin receptors, FABP4 fatty acid
binding protein 4)
may play a role in the pathogenesis of breast can-
cer that operates independent of their
well-­
­ documented function in binding the ER
molecules expressed by breast cancer cells. In
this context, despite the lack of clinical responses
of ER-negative breast cancers to tamoxifen ther-
apy, aromatase inhibitor is able to block tumor
growth. Actually, estrogen also enhances the
growth of ER-negative tumors by increasing the
systemic capacity for angiogenesis and the
recruitment of bone marrow-derived stromal
cells (Gupta et al. 2007). Breast cancer patients
25 Obesity-associated Breast Cancer: Analysis of risk factors
have increased exposure to unbound circulating
estradiol. An increased percentage of estradiol
bound to albumin may influence the availability
of estradiol, considering its low binding affinity
to albumin (Ota et al. 1986). Weight loss as a
result of caloric restriction and exercise signifi-
cantly decreases estrogens and free testosterone,
and increases sex hormone-binding globulin
(SHBG) (Campbell et al. 2012). In contrast,
increasing obesity correlates with a progressive
fall in SHBG level. Thus increasing upper body
fat localization is inversely proportional to levels
of SHBG in breast cancer patients and healthy
individuals. Premenopausal breast cancer patients
are found to have significantly lower levels of
SHBG compared with age-matched and weight-
matched individuals. Lower levels of SHBG also
result in increased levels of circulating unbound
androgens which may result in tumor progression
by themselves and further conversion to estro-
gens by adipose tissue (Schapira et al. 1991).
Thus, the levels of estradiol that are detected in
breast cancers are 50 to 100-fold higher than the
concentrations of this hormone that are found in
the circulation of postmenopausal women. The
high estradiol concentrations found in breast can-
cers could arise either due to uptake from the cir-
culation or from endogenous synthesis. Since
similar concentrations of estradiol are present in
tumors with or without estrogen receptors,
endogenous synthesis is considered to be the
major pathway by which tumor estrogens origi-
nate. Three main enzyme complexes are involved
in the synthesis of estrogens in peripheral tissues.
Firstly, aromatase is responsible for the aromati-
sation of androstenedione to estrone. Secondly,
estrone sulfatase catalyses the formation of
estrone from estrone sulfate, and finally estradiol-
17β-hydroxysteroid dehydrogenase Type 1 is
responsible for the reduction of estrone to the
biologically active estrogen and estradiol (Purohit
et al. 2002). The aromatase enzyme, estrogen
synthase (CYP19 p450), belongs to a family of
p450 enzymes (Simpson et al. 1981). In post-
menopausal women, it is located mainly in adi-
pose tissue but is also present in normal and
malignant breast tissues. Immunocytochemical
studies indicate that aromatase settles in the stro-
577
mal part of breast tumors (Sasano and Harada
1998), as well as in epithelial location. There is a
significant, but inverse, correlation between the
aromatase activity and the estrogen receptor sta-
tus, indicating the likelihood of negative estrogen
receptors if substantial aromatase activity is pres-
ent (Esteban et al. 1992). Three-fold higher
human aromatase mRNA levels are found in the
mammary gland of female mice that are fed with
a high fat diet compared with their littermates on
normal chow. Because overweight females have
twice the mammary gland mass as lean controls,
thereupon, the overweight mice could have up to
six-­fold higher human aromatase mRNA in their
mammary gland compared with lean counter-
parts. Hence, weight loss may reduce breast can-
cer risk via reduction in local aromatase
production of the breast in premenopausal obese
women (Chen et al. 2012). As mentioned above,
epithelial cells are the primary site of estrogen
synthesis in the breast and breast cancers.
Aromatase expression is detected in the cyto-
plasm of tumor epithelial cells and the surround-
ing stromal cells of over 50% of tumors. Although
intra-tumoral aromatase activity does not corre-
late with steroid receptors, ER-positive tumors
express aromatase. These data indicate that some
breast cancers synthesize sufficient estrogen to
stimulate their own proliferation (Brodie et al.
1997). Assays of aromatase levels in adipose tis-
sue from the different quadrants of mastectomy
specimens from patients with breast cancer indi-
cate that activity is always higher in breast quad-
rants associated with tumor as compared with
non-involved quadrants. These results emphasize
the importance of local estrogen synthesis within
the breast (Miller and O’Neill 1987). Loss of the
ovarian function to supply estrogen and
­progesterone after menopause can cause deregu-
lation of the body’s metabolism and the availabil-
ity of systemic estradiol dramatically decreases
(Boonyaratanakornkit and Pateetin 2015).
Elevated in situ estrogen concentrations in post-
menopausal human breast cancer patients are
derived from intratumoral aromatization.
Furthermore, in patients with estrogen-dependent
breast carcinoma, intratumoral estrogens func-
tion as an autocrine growth and a mitogenic fac-
578
tor and could impart a growth advantage to these
cancer cells, regardless of serum concentration of
estrogens (Sasano et al. 2006). Furthermore, in
postmenopausal breast cancer patients, up to
50% of deaths have been attributed to obesity
(van Kruijsdijk et al. 2009). As mentioned above,
aromatase activity is highest in adipose tissue of
the breast quadrant containing the tumor. In these
breast tissues, a significant correlation is also
found between interleukin-6 (IL-6) production
and aromatase activity (Reed et al. 1993). In
accordance with declining systemic estradiol at
menopause, the incidence of ER-alpha-positive
breast cancer dramatically increases (Pfeilschifter
et al. 2002; Sasser et al. 2007). BMI, leptin, IL-6
and reactive oxygen species (ROS) is higher in
ER positive compared with ER negative patients.
Among ER positive patients, BMI, leptin, IL-6
and ROS correlate with tumor size and metasta-
sis. Additionally, leptin, IL-6 and ROS positively
correlate also with lymph node metastasis.
Eventually, weight gain, inflammation and oxida-
tive stress are involved in post-menopausal
estrogen-­dependent breast cancer prognosis
(Madeddu et al. 2014). Evidently, obesity is asso-
ciated with a worse breast cancer prognosis, par-
ticularly in ER-alpha-positive, postmenopausal
patients. Obesity-associated systemic IL-6 indi-
rectly enhances preadipocyte aromatase expres-
sion via increased breast cancer cell prostaglandin
E2 (PGE2) production (Bowers et al. 2015).
Increased nuclear factor-kappaB (NF-kappaB)
binding activity and elevated aromatase expres-
sion and activity are found due to chronic inflam-
mation in breast tissue of overweight and obese
women. The severity of breast inflammation of
obese women is defined as the crown-like struc-
tures of the breast index and this severity status is
correlated with both BMI and adipocyte size. The
obesity-inflammation-aromatase axis is an indi-
cator of the increased risk of hormone receptor-­
positive breast cancer and is a sign of poor
prognosis in breast cancer of overweight and
obese women (Morris et al. 2011; Subbaramaiah
et al. 2012). Indeed, increased secretion of pros-
taglandins via constitutive cyclooxygenase
(COX)-1 and inducible COX-2 isozymes in the
breast cancer tissue microenvironment can result
A. Engin
in increased aromatase activity and subsequently
increased estrogen biosynthesis through auto-
crine mechanisms in breast epithelial cells and
through paracrine mechanisms in breast stromal
cells (Richards et al. 2002). Furthermore, COX-­
2-­derived PGE2 stimulates the cyclic adenosine
monophosphate (cAMP)-phosphokinase A (PKA)
signal transduction pathway that activates CYP19
transcription. Consequently, higher aromatase
expression and increased progesterone receptor
levels are observed in breast tissues of overweight
and obese women (Subbaramaiah et al. 2012).
Actually COX-2 directly regulates gene expres-
sion of specific aromatase promoter regions of
the p450 Cyp19 enzyme, aromatase and its prod-
uct, estradiol. Inhibition of COX-2 or blocking
the biological effects of PGE2 may be useful in
significantly limiting aromatase activity and pro-
liferation of human breast tumor cells despite
the presence of COX-2 protein (Prosperi and
Robertson 2006).
Estrogen or other selective estrogen receptor
modulators (SERMs) bind to the ER, a ligand-­
activated transcription factor that regulates tran-
scription of target genes in the nucleus by binding
to estrogen response element (ERE). The ER
exists in two main forms, ER-alpha and ER-beta,
which have distinct tissue expression patterns
(Mueller and Korach 2001). ERs are expressed in
white adipose tissue, and play an important role
in regulating white adipose tissue in females.
Absence of ER-alpha causes adipocyte hyperpla-
sia and hypertrophy in white adipose tissue and is
accompanied by insulin resistance and glucose
intolerance in both males and females (Cooke
et al. 2001). Obese patients have 35% higher lev-
els of estrone and 130% higher concentrations of
estradiol. Concentrations of free estradiol and
free testosterone are two to three times greater in
overweight and obese women compared with
lean-matched controls (McTiernan et al. 2003). A
traditional hypothesis for how obesity affects
breast cancer recurrence risk is based on the
mitogenic effect of excess estrogen produced in
fat cells via the enzymatic conversion of adrenal
steroids to estrogen (Dignam et al. 2003)
(Fig. 25.1). In addition, cytokines secreted by the
adipocytes can upregulate the aromatase enzyme
25 Obesity-associated Breast Cancer: Analysis of risk factors
to further increase the estrogen production, which
may stimulate breast cancer cell growth (Cleary
and Grossmann 2009). Indeed, obesity is associ-
ated with increased adipose tissue mass and aro-
matase activity, thereby aromatase inhibitors are
less effective in women who are overweight or
obese (Goodwin 2013). For women with lymph
node-negative, ER-positive breast cancer, tamox-
ifen might be offered as the best approach for the
breast cancer risk reduction among obese women,
because obesity is associated with increased risks
of contralateral breast cancer, other primary can-
cers, and overall mortality (Dignam et al. 2003).
However, in postmenopausal women with early-­
stage breast cancer and high BMI, after a median
of 8.7 years of follow-up, obesity shown to be
an independent adverse prognostic factor for
death from breast cancer. Aromatase inhibitors
are more effective than tamoxifen in reducing
overall deaths, breast cancer recurrences, and dis-
tant metastases (Ewertz et al. 2012). In any way,
risk factors associated with breast cancer reflect
cumulative exposure of the breast epithelium to
estrogen (Henderson and Feigelson 2000). Two
current hypotheses exist to explain this relation-
ship (Yue et al. 2005). In the first hypothesis;
according to genomic mechanism, estrogens dif-
fuse into the cell and bind to the estrogen recep-
tor, which is located in the nucleus. This nuclear
estrogen-ER complex binds to ERE sequences
directly or indirectly through protein-protein
interactions with activator protein 1 (AP1) in the
promoter region of estrogen-responsive genes
(Deroo and Korach 2006). Thereby, estrogen
modulates this mechanism by two separate pro-
cesses. One involves the binding of estradiol to
ER-alpha with stimulation of cell proliferation.
Consequently, errors in DNA occurring during
replication result in fixed mutations when not
repaired. The other process results from the for-
mation of genotoxic metabolites of estradiol,
which can bind to DNA, cause depurination, and
result in mutations (Santen et al. 2009). In brief,
estrogens increase the rate of cell proliferation by
stimulating ER-mediated transcription. Thus
increasing number of errors occur during DNA
replication (Yue et al. 2005). At the same time,
estrogen can act more quickly via non-genomic
579
mechanisms, either through the estrogen recep-
tor, which is located in or adjacent to the plasma
membrane, or through other non-estrogen recep-
tor, plasma membrane-associated estrogen-­
binding proteins. Eventually, estrogen-mediated
cellular responses are increased levels of Ca2+ or
nitric oxide (NO), and activation of kinases
(Deroo and Korach 2006). In the second process,
estradiol is metabolized to quinone derivatives,
which directly remove base pairs from DNA
through depurination. The third pathway involv-
ing estrogen metabolism is mediated by cyto-
chrome p450. Reactive electrophilic estrogen
o-quinones and ROS are generated through redox
cycling of o-quinones (Bolton and Thatcher 2008).
All these data indicate that both ER-dependent
and genotoxic ER-independent effects of estra-
diol mediate breast cancer development (Santen
et al. 2009). The hormonal changes across the
perimenopause and increased risk of obesity at
menopause may be caused by the decrease in cir-
culating estrogen, and, for fat distribution shifts,
the relative increase in the androgen-estrogen
ratio (Davis et al. 2012; Lovejoy 2003).
5  reast Cancer Recurrence
B
in Obesity
Obesity has been repeatedly shown to be a risk
factor for breast cancer recurrence and poor sur-
vival. In a meta-analysis of 43 studies, compared
with non-obese, obese women with breast cancer
showed to have poorer survival which is similar
for overall and breast cancer specific survival.
This association does not differ by menopausal
status (Protani et al. 2010). Adjusting for clinical
factors and potential confounders, 10% weight
gain and obesity are associated with increased
risk of late recurrence (Nechuta et al. 2016).
Compared to normal-weight women, obese
women have experience of increased risk of
recurrence and risk of breast cancer death,
12.2% and 6.9%, respectively within 10 years of
diagnosis. Although, there is no association
between BMI and all-cause mortality, obese
women have significantly faster growing tumors
(Kamineni et al. 2013). The cohort consisted of
580
3385 women enrolled in National Surgical
Adjuvant Breast and Bowel Project (NSABP)
protocol B-14 showed that obesity is not associ-
ated with an increase in recurrence risk in lymph
node-­negative, ER-positive breast cancer cases.
However, obesity is associated with increased
risks of contralateral breast cancer and of over-
all mortality (Dignam et al. 2003). In 153 case-­
control pairs of perimenopausal and
postmenopausal women, total estradiol, bio-
available estradiol and free estradiol concentra-
tions are significantly associated with risk for
recurrence. Recurred women have an average
total estradiol concentration that is double than
that of non-­recurred women (Rock et al. 2008).
Serum levels of soluble IL-6 receptor are lower
in patients with ER-positive cancer. However,
higher serum levels of soluble IL-6 receptor at
diagnosis are associated with significantly
shorter relapse-free survival in patients with
ER-positive breast cancer (Won et al. 2013).
Direct application of IL-6 on breast cancer cells
inhibits proliferation in ER-positive cells, while
high circulating IL-6 levels are correlated with a
poor prognosis in breast cancer patients
(Dethlefsen et al. 2013). Interleukins could
stimulate many signaling pathways and thus
regulate the transcription of target genes that are
involved in tumor growth, invasion and meta-
static potential (Gelaleti et al. 2012). Firstly,
estradiol antagonizes IL-6 function by repress-
ing both IL-6 and its signaling receptor, gp130
(Pfeilschifter et al. 2002). Five-­year follow-up
of 1199 women with hormone receptor positive
and human HER2-negative invasive breast can-
cer are evaluated for the impact of obesity on
time to either local or distant recurrence or new
breast cancer, or death due to breast cancer.
Moderate to severe obesity is associated with a
poorer invasive breast cancer prognosis; this is
also true for women with Stage 1 disease, and is
independent of age and treatment (Robinson
et al. 2014). Weight gain after diagnosis of
breast cancer is associated with higher all-­cause
mortality rates compared with maintaining body
weight. Adverse effects are greater for weight
gains of 10% or higher (Playdon et al. 2015).
A. Engin
Actually, high BMI is significantly associated
with larger tumor size both in pre and postmeno-
pausal women. Obese premenopausal women
show worse histopathologic features including
more metastatic axillary lymph nodes, and pres-
ence of vascular invasion, compared to under or
normal weight group. Postmenopausal patients
with BMI less than 25 develop more frequently
estrogen and progesterone receptor positive can-
cers, while no association is found in premeno-
pausal women (Biglia et al. 2013). There are no
differences in estradiol levels between lean and
obese women under aromatase inhibitors. The
known impact of obesity on recurrence risk in
women under aromatase inhibitors treatment
may not be due to incomplete aromatase inhibi-
tion (Diorio et al. 2012). Aromatase inhibitors
are less efficient at suppressing estradiol serum
levels in obese when compared with non-obese
women (Pfeiler et al. 2013). The higher levels of
estrogens in overweight postmenopausal breast
cancer patients before and during aromatase inhi-
bition may be due to the effects of BMI on estro-
gen metabolism rather than aromatization
(Lønning et al. 2014). Actually, weight gain is a
significant determinant of recurrences. In multi-
variate analyses, BMI variation more than 5.71%
is associated with higher rates of recurrences in
early-stage breast cancer patients (Fedele et al.
2014). BMI and weight gain is even more strongly
associated with fatal postmenopausal breast can-
cer. In these cases, the percentage of postmeno-
pausal breast cancer accounted for by weight
gain alone is approximately 16% and by hormone
replacement therapy alone was 5%. But when the
interaction between these variables is taken into
account, their impact is about one third of post-
menopausal breast cancers (Huang et al. 1997).
However, the effect on outcomes is not only lim-
ited to excess weight at presentation, as weight
gain after chemotherapy for breast cancer nega-
tively impacts disease-free survival, local recur-
rence, and death as well. Adjuvant chemotherapy
is associated with greater weight gain in node-­
positive, postmenopausal breast cancer patients.
The amount of weight gain appears greater for
premenopausal than postmenopausal women. It
is clear that excessive weight gain in premeno-
25 Obesity-associated Breast Cancer: Analysis of risk factors
pausal women may be associated with an increase
in the relapse risk of breast cancer and cancer-­
related deaths (Camoriano et al. 1990). Thus,
patients included 5204 Nurses’ Health Study par-
ticipants diagnosed with incident, invasive, non-­
metastatic breast cancer between 1976 and 2000;
860 total deaths, 533 breast cancer deaths, and
681 recurrences have been recorded during
median follow-up of 9 years. Weight at diagnosis
and weight gain is positively associated with
increased rates of breast cancer recurrence and
mortality (Kroenke et al. 2005). Furthermore,
during breast cancer chemotherapy, 31% of
patients present a notable weight variation which
is greater than 5% of their initial weight. In mul-
tivariate analyses, weight change more than 5%
is positively associated with an increased risk of
both recurrence and death (Thivat et al. 2010).
6  atty Acids and Breast
F key mediators of the increased risk of insulin
Cancer in Obesity
Obesity is strongly associated with changes in
the physiological function of adipose tissue, lead-
ing to insulin resistance, chronic inflammation,
and altered secretion of adipokines (van
Kruijsdijk et al. 2009). The increase in circula-
tory non-esterified fatty acids, adipose tissue dys-
function and the activation of toll-like receptors
(TLR) induce signal transduction pathways that
lead to the activation of transcription factors.
Adipocyte-macrophage-TLR4 axis might be
involved in the chronic low-grade inflammatory
process occurring in obesity. Indeed, the obesity
is associated with a marked infiltration of macro-
phages within the adipose tissue (Wolowczuk
et al. 2008). Actually, saturated fatty acids plus
TLR4 are mainly responsible for the amplifica-
tion of this inflammatory process. In this vicious
cycle, increased amount of saturated fatty acids
which are provided either by high-fat feeding or
adipocyte lipolysis could serve as ligands for
TLR4. Finally, the activated adipocytes and mac-
rophages produce more pro-inflammatory prod-
ucts (Wolowczuk et al. 2008) (Fig. 25.1). During
obesity, the enhanced production of CCL2 and
IL-1beta by the breast adipose tissue increases
581
recruitment of macrophages and the formation
of crown-like structures. The recruited macro-
phages are subsequently stimulated by CCL2 and
IL-1beta to secrete CXCL12. In this case, induc-
tion of angiogenesis supports the expansion of
adipose tissue. Macrophages promote tumor pro-
gression from ductal carcinoma in-situ to aggres-
sive breast cancers. Finally, inflammation within
the obese mammary gland contributes to angio-
genesis through a novel CCL2/IL-1beta/CXCL12
pathway that bypasses the vascular endothelial
growth factor/vascular endothelial growth factor
receptor (VEGF/VEGFR) pathway (Bowers
et al. 2015). Both the systemic and local conse-
quences of chronic adipose inflammation provide
key potential mechanistic links between obesity
and breast cancer (Iyengar et al. 2013). Adipose
tissue macrophages can comprise up to 40% of
the cells in adipose tissue of obese humans and
represent a rich source of cytokines which are
resistance associated with obesity (Uysal et al.
1997; Weisberg et al. 2003). Furthermore, TLR4
constitutes a molecular link between nutrition,
lipids, and inflammation and that the innate
immune system participates in the regulation
of energy balance and insulin resistance (Shi
et al. 2006). In this respect, saturated fatty acids
can activate TLR4 and its downstream signaling
pathways involving myeloid differentiation pri-
mary response 88/IL-1 receptor-associated
kinase/TNF receptor associated factor6 (MyD88/
IRAK/TRAF6) and PI3K/Akt. Constitutively,
active Akt is sufficient to induce NFkappaB acti-
vation and COX-2 expression (Lee et al. 2003).
In brief, obesity-inflammation axis is important
for the development and progression of breast
cancer. Macrophages forming crown-like
­structures in the breast adipose tissue correlate
with both BMI and adipocyte size (Morris et al.
2011). Necrotic adipocytes surrounded by mac-
rophages form crown-like structures in both
mammary glands and visceral fat. Saturated fatty
acids, which have been linked to obesity-related
inflammation and crown-like structures are asso-
ciated with activation of NF-kappaB and
increased levels of tumor necrosis factor-alpha
(TNF-alpha), IL-1beta and COX-2. Each of these
582
cytokines contributes to the induction of aroma-
tase in preadipocytes (Subbaramaiah et al. 2011).
Seventy-­five per cent of obese and 70% of over-
weight breast cancer patients have crown-like
structures, while among normal-weight breast can-
cer patients only 8.3% have crown-like structures.
This corresponds to an approximately nine-fold
change in crown-like structures comparing
obese patients to normal-weight women (Morris
et al. 2011).
Actually, TNF-alpha is the major mediator of
cancer related inflammation. Besides increasing
total estrogen metabolites, TNF-alpha signifi-
cantly decreases the Estrogen1 (E1)/Estrogen2
(E2) ratio due to a decrease in the level of E1
with a concomitant increase in E2 concentra-
tion. TNF-alpha increases the expression levels
of CYP1A1 and CYP1B1. Estradiol is metabo-
lized into 2-hydroxyestradiol (2-OHE2) and
4-hydroxyestradiol (4-OHE2) by CYP1A1 and
CYP1B1, respectively. These catechols undergo
further oxidation into semiquinones and qui-
nones that react with DNA to form depurinating
adducts leading to mutations, which are associ-
ated with breast cancer (Kamel et al. 2012).
Additionally, breast inflammation, as determined
by crown-like structures of the breast, is paral-
leled by increased NF-kappaB binding activity
and elevated levels of aromatase mRNA and
aromatase activity (Subbaramaiah et al. 2012)
(Fig. 25.1). NF-kappaB activation underlies
many aspects of breast cancer cell proliferation,
invasion and metastasis (Rose and Vona-Davis
2014). In this context, seventeen cytokines;
IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8,
IL-10, IL-12 [p70], IL-13, IL-17, granulocyte
colony-stimulating factor (G-CSF), granulocyte-­
macrophage (GM-CSF), interferon-gamma
(IFN-gamma), monocyte chemoattractant protein
(MCP)-1, macrophage inflammatory protein
(MIP)-1beta and TNF-alpha are expressed in
breast carcinoma, whereas only nine of these
could be detected in normal breast. Most cyto-
kines are more abundant in breast carcinoma than
in normal breast, with IL-6, IL-8, G-CSF, IFN-­
gamma, MCP-1 and MIP-1beta being very abun-
dant. IL-2, IL-6, IL-8, IL-10, IFN-gamma,
MCP-1, MIP-1beta and TNF-alpha, and to a
A. Engin
lesser extent IL-1beta and IL-13 exhibit levels of
expression that are inversely correlated to ER and
PR status. However, IL-1beta, IL-6, IL-8, IL-10,
IL-12, MCP-1 and MIP-1beta are more abundant
in high-grade tumors than in low-grade tumors.
In addition, IL-8 and MIP-1beta are expressed to
a greater degree in HER2-positive patients
compared to HER2-negative ones (Chavey et al.
2007). Obese adipose tissue-derived inflamma-
tory mediator production could exacerbate
inflammation-associated tumorigenic effects.
These mediators and adipokines such as leptin
and inflammatory cytokines with a concomitant
reduction in adiponectin are produced in both
visceral adipose tissue depots and also within
mammary adipose tissue depots. All these depots
contribute to the development of a more severe
breast cancer phenotype via stimulating breast
cancer growth, invasion and metastasis
(Dalamaga et al. 2012). n-6 polyunsaturated fatty
acid (n-6 PUFA)-derived eicosanoids are known
as pro-inflammatory and pro-carcinogenic lipid
mediators. In contrast, n-3 PUFA-derived lipid
mediators functionally oppose the synthesis and
activity n-6 PUFA-derived eicosanoids. Thereby,
several of the known risk factors of these eico-
sanoids for breast cancer may be modified by
dietary omega-3 fatty acid supplementation
(Rose and Connolly 1999). Indeed, n-3 PUFA
have been shown to concurrently target in the
multiple aspects of the obese breast cancer phe-
notype. In this respect, reduction of macrophage
adipose tissue infiltration, crown like structure
formation and down-regulation of critical adipo-
kine production are the major goals. Collectively,
increased n-3 PUFA intake could attenuate
obesity-­associated breast cancer (Monk et al.
2014). Eventually, breast cancer risk has been
found to be negatively associated with specific
n-3 PUFAs (eicosapentaenoic acid and docosa-
hexaenoic acid) and positively associated with
n-6 PUFAs (linoleic acid and arachidonic acid) in
breast adipose tissues, which are collected from
73 breast cancer patients and 74 healthy subjects
(Bagga et al. 2002). Excessive dietary intake of
n-6 PUFA versus n-3 PUFA results in a signifi-
cantly greater proportion of eicosanoids genera-
tion from n-6 PUFA (Calder 2012). Even
25 Obesity-associated Breast Cancer: Analysis of risk factors
short-term dietary intervention can lead to statis-
tically significant increases in omega-3/omega-6
polyunsaturated fatty acid ratios in plasma and
breast adipose tissue of women with high-risk
localized breast cancer (Bagga et al. 1997).
Actually, inflammatory process leads to the
induction of COX-2 expression and a consequent
elevation in prostaglandin (PG) production.
Together with other pro-inflammatory cytokines,
the eicosanoids promote further development and
growth of breast cancers by the induction of
aromatase, particularly in estrogen positive
breast cancers. Meanwhile, the more aggressive,
estrogen-­ independent tumors may develop by
direct stimulatory effect of PGE2 and lipoxygen-
ase (LOX) products (Vona-Davis and Rose 2013).
The high energy consumption is indispensable
for both primary tumor growth and secondary
tumor cell metastasis (Phoenix et al. 2010).
Thereby, most breast cancer cell types are
addicted to fatty acids, which they require for
membrane phospholipid synthesis, signaling pro-
cesses, and energy production. Expression of the
enzymes required for fatty acid synthesis is
closely linked to each of the major classes of sig-
naling molecules that stimulate breast cancer cell
proliferation (Kinlaw et al. 2016). Obesity, which
is characterized by hyperlipidemia and an eleva-
tion of circulating free fatty acids, is also associ-
ated with enhanced cancer risk (Soto-Guzman
et al. 2010). Thus, diet-induced obesity has been
shown to promote the incidence of breast cancer
development (Cleary et al. 2004a). Additionally,
fatty acid synthase is strongly associated with the
postmenopausal breast cancer. BMI and patho-
logical stage of tumor is also related to fatty acid
synthase expression of breast cancer cells (Porta
et al. 2014). By analyzing mastectomy specimen,
the amounts of glandular and fat tissue are quan-
tified in the resected breasts tissue. Adipose tis-
sue is a major component, comprising up to 56%
of the total breast volume (Vandeweyer and
Hertens 2002).
As mentioned above, linoleic acid is a dietary
n-6 PUFA that is known to induce proliferation
and invasion in breast cancer cells. It promotes
focal adhesion kinase and Src activation, as well
as cell migration in breast cancer cells (Serna-­
583
Marquez et al. 2013). At first, oleic acid medi-
ates the production of arachidonic acid (AA),
and then AA metabolites mediate focal adhesion
kinase phosphorylation and cell migration in
breast cancer cells. In contrast, Gi/Go proteins,
phospholipase C, LOXs and Src inhibitor pre-
vents focal adhesion kinase phosphorylation and
cell migration (Navarro-Tito et al. 2010). Insulin,
leptin, and adiponectin has no effect on oleic
acid, AA, and eicosapentaenoic acid uptake by
breast cancer cells. However, preferential uptake
of AA in breast cancer cells, and the fatty acid
uptake activity of these cells is influenced by
TNF-alpha (Kaur et al. 2009). In breast cancer,
the free oleic acid induces tumor invasion
through an epidermal growth factor receptor
(EGFR), guanosine triphosphate (GTP)-binding
proteins; Gi/Go proteins, matrix metalloprotein-
ases, PKC and Src-dependent pathway, but it is
not able to promote invasion in non-invasive
breast cancer cells (Soto-Guzman et al. 2010).
The phospholipase C, mitogenic-extracellular
signal-regulated kinase 1/2 (MEK 1/2), Src, and
PI3K/Akt signaling pathways are involved in the
proliferative signal induced by oleate. This effect
is mediated at least in part via the G protein-cou-
pled receptor (GPR) 40. Eventually, fatty acids
control breast cancer cell growth via GPR40,
and may provide a link between fat and cancer
(Hardy et al. 2005). Consequently, G-protein-
coupled cell surface receptor for long-chain fatty
acids is involved in human breast cancer cell
proliferation (Yonezawa et al. 2004). Saturated
fatty acids released from adipocytes have been
linked to obesity-related white adipose tissue
inflammation. In this respect, saturated fatty acid
stimulates Akt-dependent activation of
NF-kappaB. Later on, TNF-alpha, IL-1beta and
COX-2 levels are increased in ­ macrophages.
Release of these cytokines strongly provoke aro-
matase activity (Subbaramaiah et al. 2013).
Actually, lipid desaturation is an essential pro-
cess for cancer cell survival. Stearoyl-CoA desat-
urase mRNA and protein expression is elevated
in human breast cancers and predicts poor sur-
vival. Therefore, inhibition of stearoyl-CoA
desaturase activity could efficiently control syn-
thesis of unsaturated fatty acids and limit breast
584
tumor growth (Peck et al. 2016). Lipogenesis is
regulated by the enzyme fatty acid synthase
(FASN); and breakdown of fatty acids is regu-
lated by carnitine palmitoyltransferase-1 (CPT-I).
FASN is highly expressed in breast cancers (Puig
et al. 2008). Basal expression of rate-limiting
enzymes FASN, stearoyl-CoA desaturase and
lipolytic phospholipase A2 group IVB, as well as
lipogenesis transcription factors peroxisome pro-
liferator activated receptors alpha (PPARalpha),
sterol regulatory element binding factor 2
(SREBF2) and cAMP responsive element modu-
lator (CREM) are higher in breast cancer cells.
Over-expression of lectin-like oxidized-low den-
sity lipoprotein (OX-LDL) receptor-1 in breast
cancer cells also enhances cell migration, without
affecting their adherence to TNF-alpha-activated
endothelium or transendothelial migration.
Additionally, lectin-like OX-LDL receptor-1
inhibits apoptosis and stimulates cancer cell pro-
liferation through NF-kappaB signaling pathway
(Khaidakov et al. 2011). Triple negative breast
cancer cell lines show overexpression of FASN
(Giró-Perafita et al. 2016). Through a PI3K-­
dependent pathway, HER2 stimulates the FASN
promoter and ultimately mediates increased fatty
acid synthesis. Interestingly, pharmacological
inhibition of FASN preferentially induces apop-
tosis of HER2-overexpressing breast epithelial
cells relative to matched control cells (Kumar-­
Sinha et al. 2003). By contrast, blocking the
FASN leads to apoptosis of HER2-positive breast
carcinoma cells (Blancafort et al. 2015).
A high-fat diet with estrogen deprivation leads
to development of insulin resistance, which may
accelerate mammary tumor growth through the
insulin receptor-mediated Akt pathway and inac-
tivation of AMP-activated protein kinase
(AMPK) in vivo. High circulating insulin in com-
bination with increased expression of insulin
receptor in tumor tissues may result in stimula-
tion of Akt/mTOR signaling leading to the accel-
eration of breast tumor growth (Kim et al. 2015).
Janus Kinases (JAKs) are a unique class of tyro-
sine kinases that associate with cytokine recep-
tors. Upon ligand binding, IL-6, IL-4 and G-CSF
activate members of the Signal Transducers and
Activators of Transcription (STAT) family
A. Engin
through phosphorylation on a single tyrosine.
Activated STATs form dimers, translocate to the
nucleus, bind to specific response elements in
promotors of target genes, and transcriptionally
activate these genes (Heim 1999). After the acti-
vation of JAK 1 tyrosine kinase and STAT1 and
STAT3 transcription factors by IL-6, expression
of dominant negative STAT3 in the cells strongly
reduces IL-6-mediated growth inhibition but
does not prevent IL-6-induced cell migration.
IL-6 treatment leads to activation of the MAPK
and the PI3K pathways. Inhibition of MAPK or
PI3K activity reverses IL-6- stimulated migration
(Badache and Hynes 2001). The cancer cell death
signaling c-Jun N-terminal kinase (JNK) path-
way is inhibited by IL-6. Consequently, IL-6
effectively protects cancer cells from the apopto-
sis and allows for the proliferation of malignant
cells (Lin et al. 2001). Additionally, IL-6 and
TNF-alpha acts as a regulator of estrogen synthe-
sis and aromatase activity in normal and malig-
nant breast tissues (Purohit et al. 1996). Thereby,
IL-6 and IL-1 beta regulates proliferation of
breast cancer cells through estrogen production
by steroid-catalyzing enzymes in the breast tissue
(Honma et al. 2002) In this respect, serum IL-6
concentration is significantly higher in patients
with breast cancer compared to healthy controls.
Thus, median IL-6 serum levels are nearly ten
times higher in patients with metastatic breast
cancer compared to those with loco-regional dis-
ease. Therefore, serum IL-6 level is the most dis-
criminative factor separating healthy controls and
the loco-regional and metastatic breast cancer
patient groups (Benoy et al. 2002). Moreover, the
patients with high IL-6 levels show significantly
poorer survival than patients with low IL-6 levels
(Zhang and Adachi 1999). Indeed, higher
­production of IL-6 is associated with worse out-
comes in breast cancer patients at high risk of
relapse, however these effects are limited to those
patients with ER-positive tumors. IL-6 may exert
its effect on breast cancer cells through hormonal
pathways (DeMichele et al. 2009). Although
both IL-6 and TNF-alpha are expressed by
adipose tissue, there are important differences in
their systemic release. In contrast to TNF-alpha,
IL-6 is released from the subcutaneous adi-
25 Obesity-associated Breast Cancer: Analysis of risk factors
pose tissue depot and thereby able to signal
systemically (Mohamed-Ali et al. 1997).
Consequently, there is a positive relationship
between IL-6 concentration and percentage of
body fat (Vozarova et al. 2001). IL-6 genotypes
may influence breast cancer risk in conjunction
with central adiposity in postmenopausal women
(Slattery et al. 2008). Interestingly, the breast
tumors of larger size and/or with lymph nodes
involvement exhibit higher levels of IL-6 in
tumor surrounding adipocytes. Adipocytes par-
ticipate in a vicious cycle, which is controlled by
cancer cells. Thus, invasive cancer cells dramati-
cally affect surrounding cancer-associated adipo-
cytes. Furthermore, cancer-associated adipocytes
modify the cancer cell phenotypes leading to a
more aggressive behavior (Dirat et al. 2011).
Deleterious function of cancer-associated adipo-
cytes is dependent on their crosstalk with inva-
sive cancer cells. Indeed, this event leads
to dramatic phenotypic and/or functional modifi-
cations of both cell types. These adipocytes
exhibit delipidation and acquire a fibroblast-like
shape. A high number of cancer-associated adi-
pocytes might be predicted to be detrimental in
obesity (Tan et al. 2011). Therefore, IL-6 seems
to play a key role in the acquired proinvasive fea-
ture of breast cancer cells. Furthermore, IL-6
induces cell migration through the activation of
the MAPK pathway, acts as an anti-apoptotic fac-
tor, promotes the osteoclasts formation, and
inhibits the differentiation of dendritic cells. In
this wise, IL-6 facilitates the metastases of breast
cancer (Macciò and Madeddu 2011).
Furthermore, tumor-associated IL-1alpha and
IL-1beta are present in the tumor microenviron-
ment and may play a pivotal role in regulating
invasive cancer and ductal carcinoma in-situ
growth and metastasis (Kurtzman et al. 1999).
The presence and distribution of IL-1 cytokines
and its receptors (IL-1R) in human breast cancer
suggests that the local expression of IL-1 results
in the activation of a population of cells within
the human breast cancer microenvironment. This
activation of the IL-1/IL-1R cytokine family via
autocrine and/or paracrine mechanisms leads to a
585
cascade of secondary pro-tumorigenic cytokines
(Pantschenko et al. 2003) (Fig. 25.1).
Adipocyte fatty acid binding protein 4
(FABP4) is a key adipokine for fatty acid trans-
port. Exogenous FABP4 enhances the proliferation
of breast cancer cells and induces the Akt and
MAPK signaling cascades. The inhibition of
these pathways reduces the exogenous FBAP4-­
mediated cell proliferation (Guaita-Esteruelas
et al. 2016). Although serum adipocyte-FABP
(A-FABP) levels are found to be significantly
higher in obese than in non-obese women, inde-
pendent of obesity, the serum A-FABP levels are
significantly higher in breast cancer patients than
in healthy controls. Furthermore, A-FABP is pos-
itively correlated with tumor size and nodal-­
status (Hancke et al. 2010). In fact, FABP4,
adiponectin and retinol binding protein 4 (RBP4)
are most down regulated genes in breast cancer.
These genes also display strong connections with
the other molecules of lipid metabolism pathway
in breast cancer (Merdad et al. 2015).
7  diponectin and Breast
A
Cancer
Adiponectin is synthesized and secreted almost
exclusively by the white adipose tissue. AdipoR1
and AdipoR2 serve as receptors for globular and
full-length adiponectin. These receptors mediate
the increased AMPK, PPAR-alpha ligand activi-
ties, and glucose uptake and fatty-acid oxidation
by adiponectin. Obesity decreases expression lev-
els of AdipoR1/R2. Hence, adiponectin sensitivity
is reduced in obesity (Kadowaki and Yamauchi
2005). Additionally, reduced expressions of
AdipoR1/R2 in obese animals are significantly
correlated with decreased binding of adiponectin
to membrane fractions. This s­ ituation is defined as
adiponectin resistance. Increase in adiponectin
resistance in turn may play a role in worsening
insulin resistance in obesity (Tsuchida et al. 2004).
In women with low-­circulating adiponectin levels,
breast tumors may present a more aggressive phe-
notype, by large tumor size, high-histological
grade, estrogen receptor negativity, and increased
586
angiogenesis and metastasis (Mantzoros et al.
2004). Adiponectin may act on tumor cells directly
by binding and activating adiponectin receptors
and downstream signaling pathways (Barb et al.
2006). In fact, breast cancer cells can express both
AdipoR1/R2 but not adiponectin. In contrast,
women with the highest adiponectin levels have a
65% reduced risk of breast cancer (Körner et al.
2007). The analysis of 885 cases of breast cancer
revealed that adiponectin levels are not related to
the risk of breast cancer in premenopausal women,
however, lower adiponectin levels are associated
with a higher risk of breast cancer in postmeno-
pausal women (Ye et al. 2014). Thus, an inverse
association is found between adiponectin and
postmenopausal breast cancer risk in 1477 inci-
dent breast cancer cases. However, a modest cor-
relation is estimated with ductal type of breast
cancer, but not lobular tumors. Adiponectin may
only influence breast cancer cell proliferation in a
low estrogen environment (Tworoger et al. 2007).
Nevertheless, the frequency of lymph node metas-
tasis of tumor is significantly increased in the
patients with low plasma adiponectin levels.
Furthermore, the frequency of tumors with nega-
tive estrogen receptor is significantly increased in
the patients who have less than the median adipo-
nectin level (Kang et al. 2007) (Fig. 25.1).
The highest high molecular-weight adiponec-
tin levels and lower BMI have shown a signifi-
cantly reduced risk of breast cancer in both pre
and postmenopausal women in a case-control
study, including 66 sets of Japanese female breast
cancer cases and age and menopausal status
matched controls (Minatoya et al. 2014). Low
total or high molecular-weight adiponectin asso-
ciates with risk of breast cancer particularly
among premenopausal and obese women. In con-
trast to cancer tissue, adiponectin expression is
elevated in adjacent non-tumor adipose tissues of
breast, compared with controls. In both tumor tis-
sue samples and breast cancer cell lines, AdipoR1
expression is two to four times higher than that of
AdipoR2 (Körner et al. 2007). Adiponectin
decreases breast cancer cell proliferation by
inhibiting the entry into S-phase without inducing
apoptosis, and this inhibitory effect is mediated
A. Engin
through AdipoR1 (Nakayama et al. 2008). In con-
trast, adiponectin also triggers cellular apoptosis
in breast cancer cells in the presence of 17-beta
estradiol. A cross-talk between adiponectin and
estrogen receptor signaling exists in breast cancer
cells (Pfeiler et al. 2008). Higher circulating lev-
els of leptin found in obese subjects could be a
growth-enhancing factor, whereas low adiponec-
tin levels in obese women may be permissive for
growth-promoting effect of leptin. In any case,
estrogen and its receptors have a definite impact
on the response of human breast cancer cell lines
to leptin and adiponectin (Grossmann et al. 2010).
Obesity leads to altered expression profiles of
various adipokines and cytokines including leptin,
adiponectin, IL-6, TNF-alpha and IL-1beta. The
increased levels of leptin and decreased adiponec-
tin secretion are directly associated with breast
cancer development (Khan et al. 2013). The
leptin/adiponectin ratio provides significant
adjunctive information to the risk of metabolic
syndrome beyond homeostatic model assessment-
insulin resistance (HOMA-IR)) alone (Yoon et al.
2011). In patients with breast cancer, extracellular
leptin is higher and adiponectin is lower in tumors
than in normal adjacent breast tissue. While estro-
gen exposure increases leptin secretion in post-
menopausal group, tamoxifen treatment increases
adiponectin and decreases leptin and the leptin/
adiponectin ratio (Morad et al. 2014). A signifi-
cant reduction in tumor volume is observed in
human ER-alpha-­ negative breast cancer cells,
which are pretreated with adiponectin, whereas an
increased tumor growth is evident in the human
ER-alpha-positive breast cancer cells. Cyclin D1
mRNA and protein levels are also up-regulated in
ER-alpha-positive cells by adiponectin (Mauro
et al. 2015). Actually, exogenous adiponectin may
induce the inhibition of cell proliferation and pro-
motion of apoptosis in breast cancer cells (Chen
and Wang 2011). Conversely, breast cancer aris-
ing in women with the low serum adiponectin lev-
els are more likely to show a biologically
aggressive phenotype (Miyoshi et al. 2003).
Since, adiponectin acts directly on breast cancer
cells by inhibiting proliferation and angiogenesis
or by stimulating apoptosis, it is proposed that
25 Obesity-associated Breast Cancer: Analysis of risk factors
replacement of adiponectin may be of major
importance in the prevention and the treatment of
breast cancer in obese patients (Delort et al. 2012).
Consequently, serum adiponectin levels in
ER-negative/PR-negative breast cancer show an
inverse relationship with the risk of recurrence
(Oh et al. 2011).
8 Insulin Resistance
and Insulin-Like Growth
Factor in Breast Cancer
The association of insulin with breast cancer
outcomes is nonlinear. Insulin resistance is sig-
nificantly correlated with obesity, which is asso-
ciated with distant recurrence and death
(Goodwin et al. 2002). This connection between
insulin resistance and obesity is strongly valid
for only postmenopausal patients with high pro-
liferative luminal B/HER-2-negative type of
breast cancer (Nam et al. 2016). Evaluation of 22
studies with 7478 cases indicated that fasting
insulin and non-­fasting or fasting C-peptide lev-
els are not different between women with and
without breast cancer, whereas HOMA-IR levels
in breast cancer patients are significantly higher
than in women without breast cancer (Hernandez
et al. 2014). In this respect, hyperinsulinemia is
a consequence of insulin resistance or the
impaired responsiveness of cells to insulin. This
metabolic imbalance is more common in obese
women than in normal-weight women (Lazarus
et al. 1998). Evaluation of 816 randomly chosen
postmenopausal breast cancer cases revealed
2.4-fold increase in breast cancer incidence in
women with the highest quartile of fasting insu-
lin concentrations. Ultimately, hyperinsulinemia
and insulin or insulin like growth factor-1 (IGF-
1)-signaling are independent risk factors for
breast cancer and may have a substantial role in
explaining the obesity-breast cancer relationship
(Gunter et al. 2009). Actually, IGFs are mito-
genic and anti-apoptotic peptides that influence
the proliferative behavior of many cell types,
including normal and transformed breast epithe-
lial cells. IGF binding proteins (IGFBPs), and
IGFBP proteases regulate circulating IGF-I lev-
587
els (Pollak 1998). Circulating insulin levels and
plasma levels of IGFBP-3 are simultaneously
elevated in women with premenopausal breast
cancer (Del Giudice et al. 1998). Approximately
1% of circulating IGF-1 remains unbound, while
the rest is mainly bound to IGFBP-3 (Pollak
2008). IGFBP-­binding to cell surface results in
the release of more IGF to the receptors
(McCusker et al. 1990). Secretion of IGFBP-1
and IGFBP-2 is further suppressed by insulin
and is diminished with increasing obesity
(Hoeflich and Russo 2015). The insulin-cancer
hypothesis postulates that chronic hyperinsu-
linemia is associated with decreased concentra-
tions of IGFBP-1 and IGFBP-2, leads to
increased availability of IGF-1 and concomitant
changes in the cellular environment that favor
tumor formation (Renehan et al. 2006). The
IGF-1 and IGFBP-2 are amongst the most potent
mitogens for mammary epithelial cells and there
are accumulating evidences that they interact
with the estradiol-axis to regulate mitogenesis,
apoptosis, adhesion, migration and differentia-
tion of mammary epithelial cells. Such interac-
tions are bi-directional and estradiol has been
shown to regulate the expression and activity of
IGF-axis genes with the general effect of sensi-
tizing breast epithelial cells to the actions of
IGFs and insulin (Hawsawi et al. 2013). IGF-1
can specifically target its receptors on human
breast epithelial cells to induce mitogenic and
anti-apoptotic pathways. Both the PI3K and
MAPK pathways are important for IGF-1-­
stimulated proliferation of human breast cancer
cells in vitro. Insulin-receptor substrate (IRS)-1,
but not IRS-2, is the predominant signaling mol-
ecule activated by IGF-I and insulin (Jackson
et al. 1998). For overall survival of breast cancer
patients, only histological grade and IGF-1R
mRNA emerges as significant predictors.
Increased IGF-1R mRNA implies poorer prog-
nosis among the different subtypes of breast can-
cer, and that may be associated with the lack of
responsiveness to tamoxifen in cases with a posi-
tive hormone receptor status (Peiró et al. 2011).
In contrast, IGF-1R correlates with good prog-
nostic markers among patients with early breast
cancer and is differentially expressed with vari-
588
able prognostic impact among breast cancer sub-
types (Yerushalmi et al. 2012). However, IGF-2
is expressed both in the epithelial tumor cells
and in stromal cells, in 84% and 50% of breast
cancer cases, respectively. IGF-2 expression in
cancer cells is related to a non-metastatic disease
at diagnosis or to low tumor grade (Toropainen
et al. 1995). IGF-1R may be overexpressed in all
breast cancer subtypes, regardless of the hor-
mone receptor or HER2 status and its expression
rates range from 43.8 to 87% by Allred score
(Shimizu et al. 2004; Yerushalmi et al. 2012).
There is a significant correlation between
IGF-1R and ER status, but not between IGF-1R
and PR status. Patients with IGF-1R-positive
and ER-negative breast cancers are in a worse
situation than IGFR-negative ER-negative can-
cer patients (Railo et al. 1994). Within 4 years of
initial breast tumor diagnosis, elevated levels of
IGF-1R are strongly associated with ipsilateral
breast tumor recurrence. IGF-1R predisposes to
early relapses after radiation therapy, which is
thought to be true for the recurrences. After
more than 4 years, recurring tumors are more
likely to represent de novo primary breast can-
cers, therefore IGF-1R expression would not be
expected as a marker of radioresistance (Turner
et al. 1997). On the other hand, reduction of
serum IGF-1 levels results in significantly
decreased burden of tumors, despite modestly
elevated levels of circulating insulin and leptin
(Lashinger et al. 2011). In this context, IGFBP-3
induces apoptosis in an IGF-IGFR axis-indepen-
dent manner through the activation of caspases
involved in a death receptor-­mediated pathway
in human breast cancer cells. Consequently,
IGFBP-3 functions as a negative regulator of
breast cancer cell growth (Kim et al. 2004)
(Fig. 25.1). The characteristics and phenotypic
behavior of malignant breast ductal epithelial
cells associate with the synergistic activity of
adipocyte-derived factors. Adipocyte-secreted
substances can affect tumorigenesis by increas-
ing the stabilization of pro-­ oncogenic factors
(Iyengar et al. 2003). Adipocytes from subcuta-
neous adipose tissue specimens of obese indi-
viduals are capable of producing larger amounts
of IGF compared with lean women. IGF-1 is a
A. Engin
pivotal factor in adipocyte regulation of breast
cancer cell growth and it is upregulated at early
period of adipocyte differentiation (D’Esposito
et al. 2012). Indeed, obesity is associated with
significant changes in the growth hormone (GH)/
IGF system. In non-­diabetic obese subjects, adi-
pocytes produce large amount of free IGF-1 and
IGF-2, total IGF-2, IGFBP-3 and growth hormone-
binding protein (GHBP), reduced IGFBP-1 and
IGFBP-2 when compared to lean subjects.
Conversely, in obese Type 2 diabetics, free IGF-I
is insignificantly reduced, when compared to
non-diabetic obese subjects (Frystyk et al. 1999).
Adipocytes-­derived IGF-1 release is regulated
by glucose and fatty acids and may contribute to
the control of breast cancer cell growth in obese
individuals (D’Esposito et al. 2012). Actually,
IGF-1 and IGF-2 stimulate both normal growth
development and breast cancer cell proliferation.
IGF-2 induction of the aryl hydrocarbon recep-
tor (AHR) promotes the expression of Cyclin D1
and the proliferation of breast cancer cells
(Tomblin and Salisbury 2014). The AHR also
regulates cell cycle in part by binding with
Cyclin D1 and cyclin dependent kinase 4
(CDK4) in human breast cancer cells (Barhoover
et al. 2010). Adipocytes secrete IGF-2 at levels
that stimulate the proliferation of human
ER-positive breast cancer cells. By contrast, spe-
cific exogenous AHR ligands inhibit the prolif-
erative effects of mitogenic adipokines, including
IGF-2 in human ER expressing breast cancer
cells (Salisbury et al. 2013). In the absence of an
exogenous AHR agonist, the AHR is located in
the cytoplasm bound to chaperon proteins. In the
classical mechanism of AHR action, upon acti-
vation by an agonist, the AHR dissociates from
chaperon proteins, translocates into the nucleus,
and stimulates transcription by binding to AHR
response elements (AHRE) (Denison et al.
2011). AHR-­dependent gene transcription is ter-
minated by dissociation of the liganded AHR-
AHR nuclear translocator (ARNT) complex
from the dioxin-­responsive element (DRE), sub-
sequent nuclear export of the AHR into the cyto-
sol is mediated by its N-terminal nuclear export
sequence followed by ubiquitin-mediated AHR
degradation (Pollenz 2002). Although the ER
25 Obesity-associated Breast Cancer: Analysis of risk factors 589

signaling pathway has many mechanistic simi- cancer and is associated with low levels of adipo-
larities to that of the AHR, there are some differ- nectin and shorter breast cancer survival (Duggan
ences. ER isoforms are localized primarily in the et al. 2011). Actually, adiponectin and HOMA-IR
nucleus in their unliganded state and are found have also prognostic significance in breast cancer
complexed with two chaperone proteins recurrence. Treatments related to these factors
(Heldring et al. 2007). However, AHR-ER cross- may protect against recurrence in ER-negative/
talk is multifactorial in nature, effecting both PR-negative patients. Similar results could not be
ERalpha and ERbeta, and involving a combina- achieved in the case of ER-positive/PR-positive
tion of both classical and non-classical AHR- patients (Oh et al. 2011). Interestingly, an inverse,
dependent mechanisms that results in inhibition significant association between insulin resistance
of estrogen response or responsiveness. and cancer recurrence is observed in the
Eventually, induction of gene expression by the ER-positive/PR-positive breast cancer patients.
classical AHR-ARNT-DRE signaling pathway Furthermore, ER-positive/PR-positive patients
can repress ER-dependent signaling (Denison with hyperglycemia showed decreased risk of
et al. 2011). recurrence (Oh et al. 2011).
Considering breast cancers overall, the rela-
tionship between obesity and cancer risk is com-
plex. Obesity is associated with an increased risk 9 Adipose Tissue Hypoxia
of postmenopausal breast cancer. Contrarily, in in Breast Cancer
premenopausal women, obesity has no or even
reducing effect on breast cancer risk. However, Increased adipose tissue hypoxia, accompanies
epidemiologic data have demonstrated that obe- obesity. Obesity-induced hypoxia and oxidative
sity is strongly associated with an increased risk stress affect the production of many adipocyte-­
of triple-negative breast cancer in both pre- and derived proteins involved in angiogenesis,
postmenopausal women (Millikan et al. 2008). inflammation and extracellular matrix remodel-
Actually, triple-negative breast cancers are ing. All these alterations can establish a pro-­
aggressive tumors, which are typically malignant environment for breast tissues
ER-negative, PR-negative and human EGFR-2 (Yao-Borengasser et al. 2015). Cancer-associated
negative tumors and targeted therapies for triple-­ adipocytes (CAAs) are essential for breast tumor
negative breast cancers are almost currently development and progression. Furthermore,
unavailable (Toft and Cryns 2011). CAAs modify the cancer cell characteristics and
Insulin may influence prognosis to the great- phenotype as leading to a more aggressive tumor
est extent during the first 5 years after diagnosis, behavior (Dirat et al. 2011). Adipocytes can
whereas obesity-related factors, particularly modify ER gene expression and promote
leptin continue to be important with longer fol- epithelial-­mesenchymal transition in breast can-
low-­up (Goodwin et al. 2012). IGF-I activates cer cells through upregulation of hypoxia-­
downstream signaling molecules within the inducible factor 1 alpha (HIF-1alpha). Obesity
leptin receptor and IGF-1R pathways. In contrast plays an important role in the development of an
to IGFI, leptin does not induce phosphorylation aggressive breast cancer (Yao-Borengasser et al.
of IGF-1R, indicating that receptor cross-­ 2015). Decreased oxygen availability stimulates
signaling is unidirectional and signal transmis- cells to consume glucose and produce lactate.
sion occurs from IGF-1R to leptin receptor in This response is coordinated by the HIF-1,
human breast cancer cells (Ozbay and Nahta which is expressed under the control of signaling
2008). Elevated HOMA-IR scores and low levels of the PI3K/Akt/mTOR pathway in tumor cells
of adiponectin are both associated with obesity (DeBerardinis et al. 2008). A significant correla-
and increased breast cancer mortality in obese tion is demonstrated between impaired glucose
breast cancer cases. Hyperinsulinemia is an inde- tolerance and disease progression in postmeno-
pendent risk factor for poor prognosis for breast pausal women receiving treatment of breast can-
590 A. Engin

cer. In particular lactate, are predictive of reduced

derived leptin is strongly involved in mammary
response to chemotherapy and is prognostic for carcinogenesis by contributing to the local pro-­
weight gain during early breast cancer chemo- inflammatory mechanisms. Therefore, obese
therapy (Stebbing et al. 2012). Hyperinsulinemia patients with breast cancer have increased meta-
could induce breast cancer progression through static potential and greater risk of mortality
leptin-dependent mechanisms. Thus, insulin (Delort et al. 2015). Serum leptin levels and
stimulated leptin expression is associated with leptin/BMI ratio are significantly increased in
increased activation of the leptin gene promoter. patients with breast cancer (Romero-Figueroa
Excess insulin increases nuclear accumulation et al. 2013). In the primary breast cancer cases,
of transcription factors HIF-1alpha and their expressions of leptin and leptin receptor are
loading on the leptin promoter (Bartella et al. found in 85% and 75%, respectively. In these
2008). Furthermore, serum lactate inhibits lipol- cases, the expression of leptin is significantly
ysis and triglyceride breakdown in adipocytes correlated with leptin receptor. Additionally,
through a direct activation of the orphan leptin receptor expression in primary breast can-
G-protein-coupled receptor, GPR81(Liu et al. cer is positively correlated with estrogen receptor
2009). Breast cancer cells can switch to a form expression and tumor size but not with Ki67 or
that can utilize lactate as a primary source of progesterone receptor expressions (Jardé et al.
energy, allowing them to survive in case of glu- 2008). Both normal epithelial cells and carci-
cose deprivation and this activity confers resis- noma cells express leptin. However, overexpres-
tance to PI3K/mTOR inhibitors. Estrogen-related sion of leptin is observed in 92% of invasive
receptor alpha (ERR-­alpha), is shown to regulate ductal carcinomas but in no normal epithelium.
the expression of genes required for lactate utili-
Furthermore, normal mammary epithelial cells
zation (Park et al. 2016). COX-2 directly regu- do not express a significant level of leptin recep-
lates gene expression of specific aromatase tor, whereas 83% of breast cancer cases have
promoter regions and regulates aromatase leptin receptors. Accordingly, distant metastasis
enzyme activity in breast cancer cells (Prosperi is detected in 34% of all leptin receptor-positive
and Robertson 2006). PGE2 also increases HIF- tumors with leptin overexpression, but none of
1alpha transcript and protein expression, nuclear the patients with leptin receptor-negative and
localization and binding to aromatase promoter- weak leptin expressing tumors are associated
II in human breast adipose stromal cells. with distant metastasis (Ishikawa et al. 2004).
Actually, HIF-1alpha as a modulator of aroma- Higher circulating levels of leptin found in obese
tase promoter II-driven aromatase expression in individuals and act as growth-enhancing factor.
human breast tumor-associated stroma and pro- In contrast, low adiponectin levels in obese
vides a special mechanism for estrogen regula- women may be permissive for leptin’s growth-­
tion in obesity-related, post-­menopausal breast promoting effects (Grossmann et al. 2010)
cancer (Samarajeewa et al. 2013). (Fig. 25.1). Leptin/adiponectin ratio are increased
significantly in the breast cancer patients, in com-
parison to controls. BMI is negatively and posi-
10 Leptin and Breast Cancer tively correlated to serum adiponectin and leptin
levels, respectively. Low serum adiponectin lev-
Adipocytes account for more than 90% of human els and high serum leptin levels are associated
breast volume and secrete adipocytokines, with an increased risk for breast cancer. The
including leptin. Breast adipose tissue-derived blood levels of estradiol increase in parallel to
leptin promotes the growth of developing breast those of leptin. The increased serum ratio of
cancer (Guo et al. 2012; Khandekar et al. 2011). leptin/adiponectin may indicate the presence of
Indeed, the breast cancer cells are surrounded by aggressive breast cancers (Chen et al. 2006).
an adipocyte microenvironment, which is more Furthermore, high leptin levels in obese and
extensive in obese people. Thus, adipocyte-­ overweight individuals are also positively corre-
25 Obesity-associated Breast Cancer: Analysis of risk factors
lated with body fat and adipocyte size. In terms
of obesity, leptin is unable to regulate appetite
and size of fat deposits leading to a “leptin resis-
tance status” (Guo et al. 2012).
Almost all of the breast cancer samples co-­
express leptin and its two main isoforms of recep-
tors, leptin receptor-L (long form) OBR-L and
OBR-S (short form) at the mRNA and protein
levels. OBR-L or OBR-S is found to be positively
correlated with the lack of progesterone receptor.
Elevated OBR-S expression has longer relapse-­
free survival, whereas high OBR-L/OBR-S is
associated with a shorter relapse-free survival in
breast cancer patients. This inverse ratio between
OBR-L and OBR-S could be a marker of tumor
aggressiveness (Révillion et al. 2006).
Actually, circulating leptin levels are propor-
tional to the body fat mass, thus serve as an adi-
posity signal of the total body energy stores.
However, despite increased leptin levels, animals
fed a high-fat diet without decreasing their caloric
intake, make them become obese. This suggests
that a high content of dietary fat changes the “set
point” for body weight, at least in part by limiting
the action of leptin (Frederich et al. 1995).
Therefore, regulating leptin sensitivity is
extremely important to control body weight. In
this respect, leptin exerts its biological action
through binding to and activating OBR-L
(Elmquist et al. 1998; Scott et al. 2009). In paral-
lel with its activation of AMPK, leptin suppresses
the activity of acetyl coenzyme A carboxylase,
subsequently stimulates the oxidation of fatty
acids in muscle. (Minokoshi et al. 2002). OBR-L
is capable of signaling to IRS-1 and MAPK via
JAK, in addition to activating STAT pathways
(Bjørbaek et al. 1997). The short isoform (OBR-­
S) is inactive in both proliferation and JAK acti-
vation. Thereby, resistance to leptin occurs
despite the presence of the OBR-S isoforms
(Ghilardi and Skoda 1997). Binding of the SH2
domain of SH2B1 to phospho-Tyr813 in JAK2
enhances the leptin induction of JAK2. Actually,
SH2B1 acts as signal transducer and signaling
adaptor in obesity and its deletion is associated
with severe obesity. Overexpression of SH2B1
enhances JAK2-mediated tyrosine phosphoryla-
tion of IRS-1 in response to leptin (Li et al. 2007).
591
SH2B1 directly binds to both IRS-1 and IRS-2
and mediates the formation of a JAK2/SH2B/
IRS-1 or IRS-2 protein complexes. Consequently,
SH2B dramatically enhances leptin-stimulated
tyrosine phosphorylation of IRS-1 and IRS-2 and
subsequent activation of the PI3K pathway (Duan
et al. 2004). mRNA expression of leptin and
leptin receptors in adipose tissue and matched
tumor samples, respectively, are associated with
obesity status in breast cancer. Increasing insulin
resistance is a predominant feature of this higher
leptin and leptin receptors expression (Carroll
et al. 2011). In response to leptin, STAT3 binds to
phospho-Tyr1138, allowing JAK2 to phosphory-
late and activate STAT3. The JAK2-dependent
and -independent pathways act coordinately and
synergistically to promote STAT3 activation
(Morris and Rui 2009). Indeed, chronic leptin
signaling causes significant phosphorylation of
JAK2 and STAT3 together with the higher breast
cancer cell proliferation rate. In addition to the
high ERalpha/ERbeta ratio, estrogen-dependent
transcriptional activity, E2-dependent cell growth
and resistance to antiestrogen agents is enhanced
(Valle et al. 2011). Activated STAT3 and G9a his-
tone methyltransferase in epigenetic silencing of
miR-200c promotes the formation of breast can-
cer stem-like cells. These cells elevate the cell
surface levels of the leptin receptors. In breast
cancer subjects with diet-induced obesity, STAT3
blockade suppresses the leptin receptor expres-
sion and inhibits tumor progression (Chang et al.
2015). Most of obese humans are characterized
by leptin resistance (Maffei et al. 1995). Leptin
specifically induces expression of SOCS-3
mRNA (Bjørbaek et al. 1998). Thus, increased
levels of SOCS-3 in peripheral tissues may there-
fore result in leptin resistance at these sites.
SOCS-3 binds to JAK2 in a leptin-dependent
manner and suggest that SOCS-3 attenuates
leptin receptor signaling by inhibiting JAK-­
induced tyrosine phosphorylation of the receptor
and of JAK itself (Bjørbaek et al. 1999).
Collectively, the deterioration of the leptin sig-
nals results in obesity. Leptin resistance in obe-
sity may occur with various mechanisms such as;
reduction in leptin transport into the brain, defects
in OBR-L trafficking, as well as in OBR-L
592
expression, increase in SOCS3 expression,
chronic endoplasmic reticulum stress by activa-
tion of various unfolded protein response-­
signaling pathways and impairment of
melanocortin-4 or brain-derived neurotrophic
factor receptors (Morris and Rui 2009).
On the other hand, in approximately 30% of
population, leptin is able to stimulate aromatase
activity in adipose stromal cells at high concentra-
tions. The elevated levels of aromatase activity
may contribute to increase in the circulating estro-
gen levels in obese women. In postmenopausal
obese women, adipose tissue is the only place of
estrogen production by aromatization of C19 ste-
roid androstenedione. Hence, the total pool of
estrogens is increased by the aromatization pro-
cess in postmenopausal obese women (Magoffin
et al. 1999). Plasma leptin levels correlate to
plasma levels of estradiol and estrone sulfate in
breast cancer patients as well as in healthy post-
menopausal females. In addition, plasma leptin
levels also correlate to total body aromatization
rate in breast cancer patients with obesity (Geisler
et al. 2007). Factors that increase endogenous
estrogen production or reduce the binding of estra-
diol to sex hormone-binding globulin may increase
a woman’s risk of developing breast cancer later in
life (Toniolo et al. 1995). On the other hand,
PPAR-gamma ligands show an inhibitory effect on
the growth of breast cancer cells. PPAR-gamma is
a member of the nuclear receptor family of ligand-
dependent transcription factors (Elstner et al.
1998). In this respect, activation of PPAR-gamma
also decreases leptin receptors, inhibits their trans-
ductional pathways, and negatively interferes with
estrogen signaling through the down-­regulation of
aromatase gene expression and the inhibition of
ER-alpha transactivation (Catalano et al. 2011).
Twenty-four per cent of 1352 total patients
with breast cancer, are classified as obese. When
the obese patients are compared with the normal
weight cancer patients, obesity is found to be
associated with non-palpable tumors, larger
tumors, a higher incidence of lymph node metas-
tasis, lower incidence of HER2 positivity, lower
incidence of multifocality (Haakinson et al.
2012). Actually, mRNA levels of the progesterone
A. Engin
receptor isoforms positively correlated with pro-
tein levels of estradiol and progesterone receptors.
The PR isoforms’ mRNA levels are inversely cor-
related with clinical-pathological markers of
tumor aggressiveness. Furthermore, the proges-
terone receptor isoforms are positively correlated
with the mRNA levels of HER/ErbB receptors
and ligands which are associated with more dif-
ferentiated phenotypes of breast cancer (Lindet
et al. 2012). An interaction between leptin signal-
ing and the transmembrane tyrosine kinase recep-
tor HER2 has been shown in breast cancer. Leptin
receptor and HER2 are co-­ expressed in these
tumors and leptin/OBR system contributes to the
enhanced HER2 activity and reduced sensitivity
to anti-HER2 treatments (Fiorio et al. 2008).
Overexpression of HER2 in a series of breast car-
cinoma cells increases the aldehyde dehydroge-
nase-expressing cancer stem cell population
which displays increased invasion and increased
tumorigenesis (Korkaya et al. 2008). Furthermore,
in different human breast cancer cell lines, leptin
enhances the expression of a chaperone pro-
tein heat shock protein 90 (Hsp90). Eventually,
HER2 protein levels are increased. In contrast,
silencing of Hsp90 gene expression by RNA
interference inhibits leptin-­mediated HER2 up-
regulation. The adipocyte-­secreted leptin modu-
lates Hsp90/HER2 expressions in breast cancer
cells. This mechanism links the obesity to breast
cancer growth and progression. However, long-
term leptin exposure reduces sensitivity of breast
cancer cells to the anti-estrogen agents (Giordano
et al. 2013). Synergy between the leptin/leptin
receptor/STAT3 signaling pathway and the HER2
receptor protects tamoxifen-treated HER2 over-­
expressing cells from the inhibitory effect of
tamoxifen through differential regulation of apop-
tosis-related genes (Papanikolaou et al. 2015).
Leptin enhances cyclin D1 gene transcription by
inducing the binding of ER-alpha to the promoter
of cyclin D1 gene. In contrast, leptin receptor
deficiency significantly enhances the inhibitory
effects of tamoxifen on tamoxifen-­ resistance-­
breast cancer cell proliferation and survival.
However, long-term endocrine therapy facilitates
leptin and leptin receptor overexpression in breast
25 Obesity-associated Breast Cancer: Analysis of risk factors
cancer cells, which attenuates the inhibitory effect
of tamoxifen by activating both the ERK1/2 and
STAT3 signaling pathways and upregulating
cyclin D1 gene expression (Qian et al. 2015).
Collectively, growth of malignant cells could
be regulated by various leptin-induced second
messengers like STAT3, AP1, MAPK and extra-
cellular signal-regulated kinases (ERKs). They
are all involved in aromatase expression, genera-
tion of estrogens and activation of ER-alpha in
malignant breast epithelium (Sulkowska et al.
2006). In this respect, leptin switches on tran-
scription of aromatase, and activates this enzyme
with engagement of AP1 promoter, STAT3 and
ERK2 by promoting estradiol synthesis (Catalano
et al. 2003). Leptin also activates ER-alpha via
the MAPK pathway (Catalano et al. 2004).
ER-alpha36 is mainly expressed on the cell sur-
face and mediates membrane-initiated or non-­
genomic estrogen signaling (Wang et al. 2005).
Hence, in ER-negative breast cancer cells Src
acts as a switch in ER-alpha36-mediated biphasic
estrogen signaling through the Src/EGFR/STAT5
pathway. Similar to ER-positive breast cancer
cells, ER-alpha36 mediates mitogenic signaling
of low-concentration estrogen through the EGFR/
Src/STAT5 pathway in ER-negative breast cancer
cells (Zhang et al. 2012). After exposure to leptin,
ER-alpha-positive breast cancer cells undergo
proliferation. This process is mediated by active
STAT3 and ERK1/2. However, elevated serum
levels of leptin maintain resistance to anti-­
estrogen drugs during hormonal therapy of breast
cancer (Garofalo et al. 2004). Despite 12 to
20-fold higher leptin levels of obese mice than
that of lean mice, malfunction leptin receptors
effectively protect against mammary tumor inci-
dence (Cleary et al. 2004b).
Actually, there is a crosstalk between Notch,
IL-1 and leptin in breast cancer. Leptin induction
of proliferation/migration and upregulation of
VEGF/VEGFR-2 in breast cancer cells are related
to an intact Notch signaling axis (Guo and
Gonzalez-Perez 2011). However, leptin upregula-
tion of VEGF/VEGFR2 is impaired by IL-1 sig-
naling blockade (Zhou et al. 2011). The notch
ligands are single-pass transmembrane proteins
593
and are members of the Delta/Serrate/LAG-2
family of proteins. Translocation of the Notch
intracellular domain into the nucleus induces the
transcriptional activation of Notch target genes.
The carcinogenesis process is reinforced by Notch
crosstalk with many oncogenic signaling path-
ways suggest that Notch signaling may be a criti-
cal drug target for breast cancer (Guo et al. 2011).
11 Conclusion
Obese women have elevated risks of ductal and
ER-positive-PR-positive breast cancer com-
pared to lean subjects. Estrogen-plus-progestin
therapy for more than 5 years significantly
increases risks of lobular and ER positive-PR
positive breast cancer compared to never users
of hormone therapy regardless of BMI. In addi-
tion, elevated estrogen concentrations in post-
menopausal breast cancer patients are largely
derived from obese adipose tissue aromatiza-
tion. Most breast cancer cell types are addicted
to fatty acids. Hence, elevation of circulating
free fatty acids in obesity is associated with
enhanced cancer risk. The obesity-inflamma-
tion-aromatase axis is an indicator of the
increased risk of hormone receptor-­ positive
breast cancer and is a sign of poor prognosis.
Increase in risk of recurrence and death in breast
cancer is significantly higher within 10 years of
diagnosis in obese women. Low-circulating adi-
ponectin levels in breast cancer patients are
associated with the increased rate of more
aggressive, high-histological grade, estrogen
receptor negative, and metastatic tumors.
Hyperinsulinemia is an independent risk factor
for poor prognosis in breast cancer, and is asso-
ciated with low levels of adiponectin and shorter
breast cancer survival in obesity. Serum leptin
levels, leptin-BMI and leptin-adiponectin ratios
are significantly higher in obese patients with
breast cancer.
Body weight control and avoiding estrogen-­
plus-­progestin therapy is an effective strategy
for primary prevention of breast cancer among
post-­menopausal women. Because of these,
594 A. Engin

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