Available online at www.sciencedirect.
com
ScienceDirect
Inflammation, dysregulated metabolism and aromatase
in obesity and breast cancer
Heba Zahid1,2,4, Evan R Simpson3,4 and Kristy A Brown1,4
Obesity is associated with an increased risk of estrogen-
dependent breast cancer after menopause. Adipose tissue
undergoes important changes in obesity due to excess storage
of lipids, leading to adipocyte cell death and the recruitment of
macrophages. The resultant state of chronic low-grade
inflammation is associated with the activation of NFkB
signaling and elevated levels of aromatase, the rate-limiting
enzyme in estrogen biosynthesis. This occurs not only in the
visceral and subcutaneous fat, but also in the breast fat. The
regulation of aromatase in the breast adipose stromal cell in
response to inflammatory mediators is under the control of
complex signaling pathways, including metabolic pathways
involving LKB1/AMPK, p53, HIF1a and PKM2. Interventions
aimed at modifying weight, including diet and exercise, are
associated with changes in adipose tissue inflammation and
estrogen production that are likely to impact breast cancer risk.
This review will present an overview of these topics.
Addresses
1
Centre for Cancer Research, Hudson Institute of Medical Research,
Clayton, Victoria, Australia
2
Faculty of Applied Medical Science, Taibah University, Medina, Saudi
Arabia
3
Centre for Endocrinology and Metabolism, Hudson Institute for Medical
Research, Clayton, Victoria, Australia
4
Monash University, Clayton, Victoria, Australia
Corresponding author: Brown, Kristy A (kristy.brown@hudson.org.au)
Current Opinion in Pharmacology 2016, 31:90–96
This review comes from a themed issue on Endocrine and metabolic
diseases
Edited by Sebastiano Andò
http://dx.doi.org/10.1016/j.coph.2016.11.003
1471-4892/# 2016 Published by Elsevier Ltd.
Obesity and breast cancer
Adipose tissue is the largest endocrine organ in the body
and plays an important role in maintaining energy ho-
meostasis. Understanding the underlying biology of adi-
pose tissue is important for understanding how obesity
contributes to tumor development. It is well known that
obesity is associated with excess storage of lipids [1]. In
addition to lipid storage, adipose tissue also produces
adipokines and steroid hormones, including estrogens.
Current Opinion in Pharmacology 2016, 31:90–96
Obesity affects the production of these factors and is
associated with a chronic state of low-grade inflammation,
having profound effects on tumor development and pro-
gression.
According to the World Health Organization, 55% of
women worldwide are overweight or obese [2]. Higher
obesity rates are associated with an increased prevalence
of obesity-associated diseases, such as cardiovascular dis-
ease, diabetes and number of cancers, including breast
cancer [3,4,5]. Breast cancer is the most diagnosed cancer
in women in developed and developing countries. In the
United States, one in eight women will be diagnosed with
breast cancer during their lifetime. Of these, two-thirds
will develop estrogen receptor-positive (ER+) tumors
that depend on estrogens for growth [6]. The main source
of estrogen in premenopausal women is the ovaries, while
in postmenopausal women, it is the adipose tissue [7].
In postmenopausal women, obesity and weight gain have
been associated with significantly higher risk of ER+/
progesterone receptor-positive (PR+) breast cancer
(Table 1; [8–10]), attributable in part to increased local
estrogen production from the breast adipose tissue. In
ER+ breast cancer survivors, a 10% increase in body
weight is also associated with increased risk of recurrence
after 5 years [11]. Additionally, higher BMI is associated
with poor prognosis and worse overall survival and breast
cancer-specific survival in women with ER+/PR+/human
epidermal growth factor receptor 2 (HER2) negative
breast cancers [12,13]. In premenopausal women, al-
though no significant effect of BMI on breast cancer risk
is observed [14], higher body mass index (BMI) is associ-
ated with larger tumors, higher incidence of lymph node
metastases and higher histological grade [15,16]. In pre
and postmenopausal women, obesity has been found to
be positively associated with breast cancer-specific mor-
tality [17,18] (Figure 1).
This review will discuss the role of obesity-associated
inflammation in driving the local expression of aromatase,
the rate-limiting enzyme in estrogen biosynthesis, via
effects on metabolic pathways.
Obesity and adipose tissue inflammation
Adipose tissue is composed of multiple cell types, includ-
ing adipocytes and cells of the stromal vascular fraction
(e.g. preadipocytes, immune and endothelial cells). In
adipocytes, a positive energy balance leads to the storage
of excess calories as triglycerides, causing their expansion.
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 Inflammation, dysregulated metabolism and aromatase Zahid, Simpson and Brown 91

Table 1

Effect of BMI on breast cancer risk in postmenopausal women.

Type of study Number of studies Years BMI (kg/m2) RR (95% CI) References
Meta-analysis 25 1997–2014 25 1.02 (0.98–1.06) [8]
30 1.12 (1.01–1.24)
35 1.26 (1.07–1.50)
Meta-analysis 11 1997–2011 Obese 1.25 (1.07–1.46) [9]
Meta-analysis 39 1980–2012 25–29.9 1.10 (1.06–1.13) [10]
30 1.18 (1.12–1.25)

With obesity, the unhealthy expansion of adipose tissue is
associated with endoplasmic reticulum stress, adipose
tissue fibrosis and localized hypoxia [1]. This, in turn,
is associated with adipocyte cell death and initiation of an
inflammatory response [19]. An increase in monocyte
chemoattractant protein-1 (MCP-1), also known as
CCL2, in adipose tissue contributes to the infiltration
of macrophages [20] and their accumulation around dead
or dying adipocytes, leading to the formation of a distinct
histological structure referred to as ‘crown like structure’
(CLS). In contrast to lean adipose tissue, which predomi-
nantly contains alternatively activated M2 macrophages,
obese adipose tissue is characterized by the infiltration of
classically activated M1 macrophages which promote
inflammation, generate reactive oxygen species and re-
lease cytokines such as tumor necrosis factor-a (TNFa)
and interleukin 6 (IL-6) [21]. Hypoxia inducible factor 1a
(HIF1a) is a key driver of this response, as loss of HIF1a
in adipocytes leads to the reduced expression of TNFa
and MCP-1 mRNA, resulting in reduced macrophage
infiltration and attenuation of the pro-inflammatory mi-
lieu [22]. The adipokine leptin, which is elevated with
obesity, also stimulates the production of TNFa, IL-6
and other cytokines, and promotes monocyte phagocytic
function (reviewed in [23]). Studies of CLS have been
undertaken in mouse models of diet-induced and genet-
ic-induced obesity, as well as in humans, where increased
weight has been shown to be associated with a greater

Figure 1

Breast
Epithelial Adipose stromal cell
Cell PGE2

cytoplasm

E2 PKA
Adipose
Stromal Cell LKB1 Aha1
Arom CRTC
p p53
p HSP90
AMPK AMPK HIF1α
p
CRTC p53
Adipose Aha1
p
Tissue CLS-B CREB HSP90
+
nucleus
- p PKM2 CRTC p
PKM2

p53 HIF1α CREB

aromatase

Current Opinion in Pharmacology

Obesity, breast inflammation and the regulation of aromatase by metabolic pathways. Obesity is associated with increased breast white adipose
tissue inflammation, characterized by an increase in the presence of CLS-B. Inflammatory mediators, including PGE2, stimulate the expression of
aromatase in adipose stromal cells via effects on metabolic pathways involving LKB1/AMPK, CREB/CRTC, p53, HIF1a and PKM2. Aromatase
catalyzes the conversion of androgens into estrogens, known to drive the growth of obesity-related breast cancer cells. Large yellow cells
represent adipocytes; blue cells represent infiltrating macrophages forming CLS. CLS-B: crown-like structure of the breast; Arom: aromatase; E2:
estradiol; PGE2: prostaglandin E2; PKA: protein kinase A; LKB1: liver kinase B1; AMPK: AMP-activated protein kinase; CREB: cAMP response
element binding protein; CRTC: CREB-regulated transcription coactivator; HSP90: heat shock protein 90; Aha1: activator of heat shock 90 kDa
protein ATPase homolog 1; HIF1a: hypoxia inducible factor-1a; PKM2: protein kinase M2.

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92 Endocrine and metabolic diseases
number of CLS/cm2 [24,25]. Interestingly, menopause is
also a determinant of breast white adipose tissue inflam-
mation [26]. The presence of CLS is associated with
activation of nuclear factor kB (NF-kB) and increased
levels of TNFa, IL-1b, IL-6, and cyclooxygenase-2
(COX-2)-derived prostaglandin E2 (PGE2) [27].
Obesity, inflammation and breast cancer:
aromatase, the missing link
Obesity and inflammation have been associated with
higher levels of aromatase in mammary adipose tissue
in both mice and humans [24,25,27,28]. Interestingly, the
presence of CLS in the mammary gland and breast (CLS-
B) appears to be more strongly correlated with aromatase
expression and activity than weight or BMI, highlighting
an important role for inflammatory mediators in driving
aromatase expression and/or potential limitations in using
BMI to define metabolic health.
The main site of aromatase expression in the breast fat is
the adipose stromal cell, a precursor to lipid-laden adi-
pocytes and often referred to as preadipocyte or fibroblast.
The stimulatory effect of inflammatory mediators on
aromatase transcript expression in isolated adipose stro-
mal cells has been described in numerous studies. In
particular, cytokines, including TNFa, IL-6, IL-11, leu-
kemia inhibitory factor (LIF) and oncostatin M, as well as
PGE2, have been shown to be potent drivers of aromatase
expression in breast adipose stromal cells [29,30]. The
mechanism of aromatase transcriptional regulation by
these factors is complex (reviewed in [31]) and con-
tinues to be the focus of investigation. For the purposes of
this review, we will present recent discoveries relating to
the role of metabolic pathways as regulators of aromatase
in the breast, as these pathways have been shown to be
dysregulated in both obesity and cancer.
Dysregulated cell metabolism and aromatase
regulation
Dysregulated cell metabolism has long been known to
occur in obesity and is now an accepted Hallmark of
cancer [32]. The role of metabolic pathways in regulating
aromatase expression in breast adipose stromal cells has
recently been explored. Initial studies examined the role
of the metabolic sensor, 50 AMP-activated protein kinase
(AMPK), and its upstream kinase liver kinase B1 (LKB1).
AMPK is well-characterized for its ability to sense
decreases in cellular ATP leading to stimulation of path-
ways of energy production and inhibition of pathways of
energy utilization [33]. LKB1/AMPK were shown to
inhibit aromatase expression in isolated adipose stromal
cells by inhibiting the nuclear entry of the CREB-coacti-
vator (cAMP response element binding protein), CRTC2
(CREB regulated transcription cofactor 2) [34]. The
obesity-associated inflammatory factor, PGE2, sup-
pressed the expression and activity of LKB1/AMPK
leading to the nuclear translocation of CRTC2 and
Current Opinion in Pharmacology 2016, 31:90–96
activation of aromatase expression. The tumor suppressor
p53, also a recently established regulator of metabolism
[35], was also found to inhibit the expression of aromatase
by binding to a p53 response element on the aromatase
promoter and be repressed by PGE2. On the other hand,
the oncogene HIF1a, also a driver of metabolic changes
in cancer cells, was found to be a potent stimulator of
aromatase expression in breast adipose stromal cells and
required for the PGE2-mediated expression of aromatase
[36]. Recently, a link between p53, HIF1a and the
metabolic regulator protein kinase M2 (PKM2) was also
demonstrated in stromal cells from Li–Fraumeni Syn-
drome patients who have elevated aromatase expression
[37,38]. It was demonstrated that loss of p53 leads to the
stabilization of HIF1a and PKM2 via heat shock protein
90 (Hsp90) dependent mechanisms, stimulates their in-
teraction with the aromatase promoter, and leads to an
increase in aromatase expression and activity. Women
with Li–Fraumeni Syndrome tend to develop ER+ breast
cancer and observed increases in breast aromatase may
account, at least in part, for why this occurs. Collectively,
these data suggest that dysregulated metabolism not only
occurs in adipocytes and cancer cells, but also in adipose
stromal cells in response to inflammatory mediators,
thereby providing a molecular link between obesity
and breast cancer.
Lifestyle interventions, inflammation,
aromatase and breast cancer risk
Considering the prevalence of obesity in today’s society
and the now established link between obesity and breast
cancer development, it is imperative that strategies are
identified to reduce the health and economic burden
predicted to occur as this population ages. As the majority
of postmenopausal breast cancers are dependent on estro-
gens for growth, it is predicted that lowering systemic and
local estrogen levels will reduce the risk of breast cancer.
A number of studies have been undertaken to examine
the effect of lifestyle interventions, including moderate
physical activity and controlled diet, on breast inflamma-
tion, estrogen levels and breast cancer risk (Table 2).
Weight loss in postmenopausal women is associated with
a reduced risk of breast cancer, while weight gain is
positively associated with risk in these women [39].
Reducing fat intake and altering diet, including increased
consumption of fruits and vegetables, has been shown to
lower the risk of relapse in women after 5 years breast
cancer treatment [40,41]. Human caloric reduction and
exercise studies have also showed improvement in weight
loss, fat reduction, overall life quality and long-term
prognosis [42,43].
In relation to effects of diet and exercise on estrogen
levels, studies have found that physical activity, alone and
in combination with improved diet, leads to a decrease in
circulating estrogens in healthy women, independent of
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 Inflammation, dysregulated metabolism and aromatase Zahid, Simpson and Brown 93

Table 2

Effect of lifestyle and pharmacological interventions on breast cancer risk, inflammatory factors and estrogen

Intervention Outcome References

Lifestyle Diet Reduced risk of invasive breast cancer [40,41,44,47]
Lower risk of relapse
Decreased levels of E1, E2, free E2 and T
Increased levels of SHBG
Decreased levels of hsCRP, SAA and IL-6
Exercise Fat loss, improved quality of life [43–45,46,47]
Decreased levels of E1, E2, free E2, A4, DHEA-S and adiposity markers
Increased levels of SHBG
Combination of Weight loss, fat reduction [42,44,47]
diet and exercise
Lowered leptin, cholesterol, saturated fat, blood pressure, hsCRP, SAA and
IL-6 Decreased levels of E1, E2, free E2 and T Increased levels of SHBG
Pharmacological Metformin Reduced cancer risk and breast cancer mortality [49–56]
Reduced PKB/Akt and ERK1/2 phosphorylation, and insulin and insulin
receptor levels
Pioglitazone Improved HDL cholesterol, biomarkers of lipid metabolism, b-cell function, [64,65]
activity of the visceral adipose tissue, and chronic systemic inflammation
Decreased total adipose macrophage number, mast cells, M1 macrophages
Increases number of M2 macrophages

E1: estrone; E2: estradiol; T: testosterone; SHBG: sex hormone binding globulin; hsCRP: C-reactive protein; SAA: serum amyloid A; IL-6: interleukin-
6; A4: androstenedione; DHEA-S: dehydroepiandrosterone-sulfate; HDL: high density lipoprotein.

menopausal status [44,45,46]. Interestingly, these
changes were dependent on loss of body fat, suggesting
that exercise reduces circulating estrogen levels originat-
ing from the adipose tissue. Similarly, the effect of diet
and exercise on adipose tissue inflammation has also been
examined. Results suggest that diet alone or in combina-
tion with exercise, leads to a reduction in systemic mar-
kers of inflammation, including C-reactive protein and
IL-6, while exercise alone did not [47]. These human
studies suggest that chronic inflammation in obese wom-
en is reversible via combinations of controlled diet or/and
exercise. In mouse models, reducing caloric intake
reverses elevations in adipose tissue inflammation and
aromatase associated with high fat feeding [48]. Specifi-
cally, 30% caloric restriction is associated with more than
75% reduction in mammary gland CLS, MCP-1 and
aromatase. Additional studies are required to determine
whether observed decreases in inflammation in women
are also associated with a decrease in the local production
of estrogens, and whether this will impact the develop-
ment and progression of breast cancers.
Pharmacological interventions, inflammation,
aromatase and breast cancer
Weight-modulating drugs, in particular anti-diabetic
drugs, have been examined for their effect on inflamma-
tion, aromatase and breast cancer (Table 2). Several
studies have described a beneficial effect of the anti-
diabetic drug metformin on breast cancer risk, recurrence
and cancer-associated mortality [49–56]. Multiple mech-
anisms have been proposed for the anti-cancer effects of
metformin, including effects on insulin and direct effects
on tumor growth, although doses required to achieve
inhibitory effects on breast cancer cells in vitro suggest
that effects observed clinically are likely to depend on
indirect effects of the drug. Metformin has also been
shown to inhibit adipose tissue inflammation in mouse
and rat models of diet-induced obesity [57–59], as well as
in subcutaneous human adipose tissue [60]. Via effects on
AMPK, metformin also inhibits aromatase transcript ex-
pression in isolated breast adipose stromal cells [61,62].
Despite being associated with weight gain, the peroxi-
some proliferator-activated receptor gamma (PPARg)
agonist and anti-diabetic drug pioglitazone, is associated
with a decrease in local and systemic inflammation in
humans when used alone or in combination with metfor-
min [63–65]. Interestingly, pioglitazone also causes a
decrease in the expression of aromatase in isolated human
adipose stromal cells and mouse mammary gland [66].
Conclusions
With a higher prevalence of obesity, it is expected that
the incidence of breast cancer will increase as the popu-
lation ages. Better understanding of the links, both phys-
iological and molecular, will allow the identification of
new therapeutic strategies to break the linkage between
obesity and breast cancer. There is a strong rationale for
targeting adipose tissue inflammation and the local pro-
duction of estrogen in order to better treat and possibly
even prevent obesity-related postmenopausal breast can-
cers.
Conflict of interest statement
Nothing declared.

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94 Endocrine and metabolic diseases
Acknowledgements
This work was supported by the Victorian Government Operational
Infrastructure Support Program. KAB is supported by the Mavis Robertson
Fellowship from the National Breast Cancer Foundation (ECF-16-004).
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