Estrogen and Cancer

Estrogen and Cancer
Jing Liang1,2 and Yongfeng Shang1,2,∗

1
Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular
Biology, Tianjin Medical University, Tianjin 300070, China; email: yshang@tmu.edu.cn
2
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education),
Annu. Rev. Physiol. 2013.75:225-240. Downloaded from www.annualreviews.org
Department of Biochemistry and Molecular Biology, Peking University Health Science Center,
Beijing 100191, China; email: yshang@hsc.pku.edu.cn
Access provided by 45.71.6.13 on 11/27/18. For personal use only.
Annu. Rev. Physiol. 2013. 75:225–40 Keywords

First published online as a Review in Advance on estrogen receptor, breast cancer, tamoxifen, endocrine resistance
October 8, 2012
The Annual Review of Physiology is online at Abstract

http://physiol.annualreviews.org
Estrogen exhibits a broad spectrum of physiological functions ranging from
This article’s doi: regulation of the menstrual cycle and reproduction to modulation of bone
10.1146/annurev-physiol-030212-183708
density, brain function, and cholesterol mobilization. Despite the beneficial
Copyright c 2013 by Annual Reviews. actions of endogenous estrogen, sustained exposure to exogenous estrogen is
All rights reserved
a well-established risk factor for various cancers. We summarize our current
∗
Corresponding author understanding of the molecular mechanisms of estrogen signaling in normal
and cancer cells and discuss the major challenges to existing antiestrogen
therapies.
225
PH75CH10-Shang ARI 15 January 2013 20:30
ESTROGEN METABOLISM IN NORMAL AND CANCER CELLS

Estrogen sex steroid hormones exhibit a broad spectrum of physiological functions ranging from
E2: estradiol regulation of the menstrual cycle and reproduction to modulation of bone density, brain function,
LH: luteinizing and cholesterol mobilization (1–3). Despite the normal and beneficial physiological actions of
hormone endogenous estrogen in women, abnormally high estrogen levels are associated with the increased
FSH: follicle- incidence of certain types of cancer, especially those of the breast and endometrium. In 1991, the
stimulating hormone Women’s Health Initiative (WHI) research program initiated a 15-year study aimed at evaluating
GnRH: the beneficial effects of postmenopausal hormone replacement therapy (HRT) on heart diseases,
gonadotropin- bone fractures, and cancers; 161,808 generally healthy women of ages 50–79 were enrolled in this
releasing study. The WHI was terminated prematurely in 2002 due to the increased incidence of breast
hormone cancer, stroke, and cardiovascular complications in women treated with estrogen alone or with
AIs: aromatase a combination of estrogen and progestogen (4). Shortly afterward, the US National Toxicology
inhibitors Program made the unprecedented decision to classify estrogens as carcinogens. The International
Agency for Research on Cancer (IARC) also listed both estrogen and estrogen-progestogen-
combined postmenopausal therapies as known human carcinogens. In this review, we focus on
the mechanisms of estrogen action in carcinogenesis and discuss current antiestrogen strategies
in cancer treatment. Due to space constraints, we apologize in advance to the many outstanding
researchers whose work we cannot cite.
The predominant intracellular estrogen is 17β-estradiol (E2). Other types of estrogen include
estrone (E1) and estriol (E3) (Figure 1a). In premenopausal women, E1 and E2 are secreted
primarily by the ovaries during the menstrual cycle, with minor levels derived from adipose tis-
sue and the adrenal glands. The placenta also produces E3 during pregnancy. In the ovaries,
granulosa cells synthesize estrogen from androgen (5). Ovarian production of estrogen is regu-
lated by the hypothalamic-pituitary-ovarian (HPO) axis and begins by anterior pituitary release
of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in response to the hy-
pothalamic peptide gonadotropin-releasing hormone (GnRH). Acting in concert, LH stimulates
androgen production, whereas FSH upregulates aromatase, which catalyzes the rate-limiting and
final step of estrogen biosynthesis: the aromatization of androgen to estrogen. During ovula-
tion, E2 production rises dramatically by eight- to tenfold. High levels of estrogen in turn act
via negative feedback to dampen estrogen production to inhibit the release of GnRH, LH, and
FSH (6).
The primary mediator of estrogen biosynthesis in postmenopausal women is aromatase, which
is found in adipose tissue as well as in the ovaries, placenta, bone, skin, and brain (7, 8). After
menopause, ovarian estrogen biosynthesis is minimal, and circulating estrogen is derived prin-
cipally from peripheral aromatization of adrenal androgen. As such, for obese postmenopausal
women, adipose tissue becomes the main source of estrogen biosynthesis; this biosynthetic route
is far less significant for nonobese postmenopausal women (9). Although aromatase is critical to
maintaining normal estrogen levels in both premenopausal and postmenopausal women, these
groups respond differently to aromatase inhibitors (AIs), which are used as antiestrogen therapy
to treat breast cancer. In premenopausal women, the HPO axis is functional, with estrogen levels
changing dramatically throughout the menstrual cycle. As a result, the effects of AIs are quickly
overridden when estrogen biosynthesis is driven by the next cycle of GnRH, LH, and FSH secre-
tion. Thus, AIs are much more efficacious in postmenopausal women, whose HPO axis is no longer
active. In men, the testes also produce significant amounts of aromatase, allowing for androgen
aromatization and estrogen synthesis (10).
Numerous studies have demonstrated the association of estrogen with the development and/or
progression of various types of cancer, including cancers of the breast, endometrium, ovary,
226 Liang · Shang

a OH OH O
OH
HO HO HO
Estradiol Estriol Estrone
CH3
N
N
O N
CH3 O
Cl O
H3C
OH
HO
Tamoxifen Toremifene Raloxifene
b AF-1 DBD LBD

A/B C D E F
AF-2
Figure 1
(a) The chemical structures of estrogens and selective estrogen receptor modulators. (b) The functional domains of estrogen receptor
(ER). Both ERα and ERβ possess six distinct domains (A–F). The N-terminal A/B domain encodes a hormone-independent
transcriptional activation function (AF-1). The AF-1 domain is responsible for the major functional difference between ERα and ERβ.
Domain C corresponds to the highly conserved DNA-binding domain (DBD). Region D, the hinge region, separates the DBD and the
ligand-binding domain (LBD). Region E encodes the LBD, which is located close to the C-terminal portion. Regions E and F also
harbor a second transcriptional activation function domain (AF-2), which activates transcription in response to estrogen.
prostate, lung, and colon (3, 11). Estrogen is a classical etiological factor for breast cancer and
endometrial cancer, and most of our current knowledge of estrogen action comes from clinical
and laboratory studies of these two types of cancer.
MOLECULAR MECHANISMS OF ESTROGEN ACTION

Estrogen mediates its biological effects in target tissues primarily by binding to specific intracellular
receptors, estrogen receptor (ER)α and ERβ. Since the initial reports of ER more than 50 years
ago (12), tremendous efforts have been made to decipher the complex molecular mechanisms of
estrogen-ER action. In the classical model of estrogen-ER function, the complex acts as a ligand-
activated transcription factor to regulate the expression of multiple target genes. An alternative
view is that estrogen exerts rapid, stimulatory effects on intracellular signal transduction pathways.
This nongenomic pathway begins outside the nucleus and is independent of gene transcription
(13–15).
ERα and ERβ are encoded by ESR1 and ESR2, respectively; each gene is located on a different
chromosome. ERα and ERβ are widely expressed in many tissues, such as the uterus, ovary, ER: estrogen receptor
mammary gland, prostate, lung, and brain. The expression levels and subtypes of ER are primary
www.annualreviews.org • Estrogen and Cancer 227

factors that determine tissue-specific estrogen responsiveness (16, 17). Both ERα and ERβ are
members of the nuclear hormone receptor superfamily of ligand-regulated transcription factors
that contain modular structures and discrete functional domains (Figure 1b). ERα and ERβ
DBD: DNA-binding
domain are highly homologous (∼96%) in their DNA-binding domains (DBDs) and possess moderate
(53%) sequence identity in their ligand-binding domains (LBDs). The major functional difference
LBD: ligand-binding
domain between ERα and ERβ appears to be determined by the hormone-independent transcriptional
activation function (AF-1) domains in their respective N termini (18). The pro-oncogenic effect
EREs: estrogen
response elements of estrogen is mediated primarily by ERα activation of target genes that promote cell proliferation
or decrease apoptosis.
HAT: histone
acetyltransferase The binding of estrogen to ERs induces conformational changes in protein structure that allow
receptor dimerization and interaction with coactivators. In some cases, the activated estrogen-ER
PTMs:
posttranslational complex directly binds to estrogen response elements (EREs) in gene promoters, leading to
modifications the transcriptional activation of target genes. Alternatively, the estrogen-ER complex indirectly
activates gene transcription through protein-protein interactions with other transcription factors
such as activator protein 1 (AP1), specificity protein 1 (SP1), nuclear factor-κB (NF-κB), cAMP
response element–binding protein (CREB), runt-related transcription factor 1 (RUNX1), p53,
and signal transduction and activator of transcription 5 (STAT5) (2, 19–22). Interaction with
other transcription factors allows the estrogen-ER complex to regulate target genes whose
promoters do not harbor a bona fide ERE.
The relative abundance of ERα versus ERβ in a given cell type appears important for medi-
ating tissue-specific estrogen responsiveness (16). ERβ was discovered in 1996, almost 40 years
after the initial characterization of ERα (18). Genetic and pharmacological lesions directed
against either ERα or ERβ show that these two estrogen nuclear receptors exert opposing effects
on cell proliferation and apoptosis (23–26). Another variant of ERα, the truncated ERα-36,
appears to mediate membrane-initiative effects of estrogen signaling, and as does ERβ, ERα-36
interferes with ERα activity, as well as with antiestrogen treatment of breast cancer (27). A recent
review summarized various ER subtypes and their roles in cancer biology and therapy (16).
To gain full transcriptional regulatory activity, the estrogen-ER complex needs to recruit
diverse transcriptional coregulators, many of which have various enzymatic activities to modify
chromatin structures or to interact with the general transcription apparatus. More than 300 pro-
teins have been shown to interact with one or more members of the nuclear receptor superfamily,
and many of these proteins also interact with ER (13, 28). The p160 family proteins (or SRCs),
including three distinct but related homologous members—SRC-1, SRC-2 (GRIP1), and SRC-3
(AIB1)—are the best-characterized coregulators of ER (29). SRCs facilitate a transcriptionally
permissive environment through direct and/or indirect recruitment of other coactivators that
have chromatin-remodeling and histone modification activities. In addition, SRC proteins possess
intrinsic but weak histone acetyltransferase (HAT) activity and mediate transcriptional activation
by directly acetylating conserved lysine residues on histones and possibly other coregulators (30,
31). Although all three SRCs directly interact with ER, they recruit different sets of secondary
cofactors to further fine-tune the transcriptional regulatory activity of the ER-nucleated apparatus
(32). The assembly and disassembly of the ER complex are extremely dynamic, and variation in
gene expression among tissues under different conditions can greatly affect the final composition
of the ER complex.
ERs, as well as their coregulators, are subjected to a variety of posttranslational modifications
(PTMs), which further influence the stability, subcellular localization, transactivity, and hormone
sensitivity of the ER-nucleated transcriptional apparatus. Approximately 22 sites throughout
ERα are subjected to various modifications, including phosphorylation, methylation, acety-
lation, sumoylation, and ubiquitination. For example, ER phosphorylation by several kinases,
228 Liang · Shang

such as mitogen-activated protein kinase (MAPK) and protein kinase A (PKA), enhances ER
transcriptional activity (33, 34); ER acetylation by the HAT p300 regulates ER transactivity
and hormone sensitivity (35); and ER ubiquitination leads to ER degradation and thus reduces
ER bioavailability (36). A recent comprehensive review summarizes the different types of ER
PTMs and their biological functions (37). Besides ER, various coregulators are also subjected
to PTMs. PTMs of coregulators change their protein conformation and greatly affect the
subunit composition, potency, and target selectivity of the final ER complex. For example,
coactivator-associated arginine methyltransferase 1 (CARM1), a well-established coactivator of
ERα and a type I protein arginine methyltransferase, catalyzes asymmetric dimethylation of
arginine residues (38). Substrates of CARM1 include histone H3 (39), the ER-interacting HATs
CBP and p300 (40), the p160 family member AIB1 (41), and the C-terminal domain of RNA
polymerase II (42). Accordingly, CARM1 regulates ERα-mediated gene transcription in multiple
ways from changing local chromatin structures to affecting the general transcription apparatus
and specific cofactors. PKA phosphorylates CARM1. Whereas unphosphorylated CARM1 binds
to ERα in the classic ligand-dependent manner, phosphorylated CARM1 binds to the unliganded
LBD of ERα and regulates the expression of different sets of genes (43).
Many genes involved in multiple intracellular pathways are directly regulated by the large
estrogen-ER transcription apparatus. Over the past several years, several groups have sought
to identify all ER target genes in the genome to fully understand the biological functions of
estrogen.
Prior to genomic approaches, a hypothesis-driven, candidate gene approach yielded some well-
characterized ER target genes, such as trefoil factor 1 (TFF-1, also known as pS2) and cathepsin D,
that have been used to delineate the molecular mechanisms of estrogen signaling (44). The rapid
advancement of array-based technology and next-generation sequencing has greatly facilitated the
identification of novel ER target genes. Data obtained by these technologies have transformed
our perception of the way that ER functions (Figure 2). In the conventional view, ligand-bound
ERs function at the promoter regions of target genes. Genome-wide mapping of ER-binding
sequences of human chromosomes 21 and 22 by using ChIP-tilling arrays indicates that the
majority of the ER-binding sites are distant (as far as several hundreds of kilobases away) from the
transcription start sites of regulatory genes and that these distal ER-binding domains often function
as transcriptional enhancers. Moreover, many of these binding sites lack a consensus ERE but are
also bound by Forkhead protein FoxA1, which is obligate for a genuine ER-chromatin interaction
(45, 46). ChIA-PET (chromatin interaction analysis using paired-end tag sequencing) technology,
which couples chromosome conformation capture with high-throughput sequencing, allows for
the global identification of three-dimensional chromatin loops formed in cells upon estrogen
induction. Treating hormone-deprived MCF-7 breast cancer cells with estrogen for a short period
yields 689 ER-associated chromatin interaction complexes, which are made up of duplexes and
more complex interactions. By combining the ChIA-PET data with gene expression profiles,
Fullwood et al. (47) discovered that a significant percentage of these clusters are transcription
hot spots induced by estrogen. The actual anchor points in these clusters can be separated by
hundreds of kilobases or even by megabases in linear two-dimensional chromatin, suggesting that
long-range chromatin interactions between DNA elements play key roles in estrogen-induced
transcriptional regulation (47).
Although ERα and ERβ have similar affinities for E2 and bind similar DNA response elements,
each receptor exhibits a unique genomic signature (45, 46, 48). Genomic profiling and ChIP-Seq
studies find that gene networks involved in cell proliferation are activated differently by these two
estrogen receptors, implying that a balance of ERα and ERβ signaling ultimately determines how
estrogen acts.

E2 E2 E2
E2
E2
E2 Plasma membrane
E2
ER
ER
E2
E2
CoA
CoA ER Nuclear membrane
CoA
ER ER CoA ER
E2
E2 E2 E2
ERE
Promoter
ER
ER ER CoA
E2
E2 E2
ERE
ER Enhancer
CoA ER
E2
E2 CoA
Sp1 Ap1
ER ER CoA
Promoter
FoxA1 E2 E2
ERE
Enhancer
Figure 2
Molecular mechanisms of estrogen-induced gene transcriptional regulation. E2 diffuses into the cell and binds to ER (ERα/ERβ).
Liganded receptors enter the nucleus and form homo- or heterodimeric complexes that bind to estrogen-response elements (EREs) on
the target gene promoters. Liganded receptors can also act as monomers and bind to target gene promoters through interaction with
other transcription factors such as Sp1 and Ap1. Promoter-associated ERs initiate gene transcription through interaction with
coregulators and the basal transcriptional machinery. Researchers recently found that ER can bind to enhancer elements far distally
from target genes regulated by ER. In some cases, the presence of the pioneer factor FoxA1 is necessary for ER to bind to its DNA
response element.
ESTROGEN SIGNALING IN CARCINOGENESIS

Mechanistic studies have established a solid foundation for our understanding of estrogen signaling
in carcinogenesis. Genetic changes associated with the oncogenic effects of estrogen match well
with the classic genetic markers of human cancers. Indeed, the activated estrogen-ER complex
regulates various genes that play key roles in cell proliferation and cell cycle progression. The
mitogenic effects of estrogen are particularly clear at the G1 -to-S transition, during which the
key effectors of estrogen action are c-Myc and cyclin D1 (49, 50). One of the earliest responses
to estrogen is increased c-Myc expression, which occurs within 15 min of estrogen stimulation.
Estrogen also rapidly induces cyclin D1 expression, and antiestrogen agents have a converse
230 Liang · Shang

acute, inhibitory effect. Inhibition of c-Myc or cyclin D1 activity abrogates estrogen-stimulated

breast cancer cell proliferation, whereas induction of c-Myc or cyclin D1 can mimic the effects
of estrogen and reinitiate cell cycle progression in antiestrogen-arrested cells (51). Although the
genes encoding c-Myc and cyclin D1 have been well established as estrogen-induced genes for
more than 20 years, the underlying molecular mechanisms of estrogen action on these two genes
are still not fully understood. In the case of the c-Myc gene, it was originally proposed that an
atypical estrogen-responsive region in the c-Myc proximal promoter is the cis element where
activated ER binds and functions. However, recent studies indicate that cooperation between
ER and AP1 at a distal enhancer element upstream of the transcriptional start site of c-Myc is
responsible for estrogen-induced c-Myc expression (52). Unlike ERα, ERβ inhibits estrogen-
induced cell proliferation. Forced expression of ERβ in ERα-positive breast cancer T47D cells
inhibits the proliferative responses to E2, possibly by suppressing the expression of cyclin E but
not that of cyclin D1 (53).
Estrogen inhibits apoptosis by upregulating antiapoptotic Bcl-2 and Bcl-XL expression in breast
cancer cells (54). The estrogen-ERα complex interacts with proteins such as c-Src through nonge-
nomic action and activates the MAPK and PI3K/Akt pathways, which are classically linked to cell
survival (19). Paradoxically, estrogen induces apoptosis under certain circumstances. Before the
introduction of tamoxifen, high-dose estrogen was used to induce tumor regression of hormone-
dependent breast cancer in postmenopausal women. This regimen is of clinical interest, given that
long-term treatment of breast cancer with antiestrogen tamoxifen often leads to drug resistance
and that sustained tamoxifen exposure may sensitize breast cancer cells to high-dose or even low-
dose estrogen therapy (55). The mysterious dual effects of estrogen on apoptosis may be due to
altered global gene expression and to redirected intracellular signaling after long-term hormone
deprivation (56, 57).
The rapid growth and division of tumor cells require sufficient nutrient supply from blood via
angiogenesis. Angiogenesis involves several steps, including the degradation of existing vascular
basement membrane, the proliferation and migration of endothelial cells into tubular structures
in the tissue, and the formation of new matrix around neovessels. Estrogen induces blood vessel
formation in the uterus during menstrual cycle. In breast cancer cells, E2 stimulates the secretion
of interleukin 8 and vascular endothelial growth factor, both potent inducers of angiogenesis.
In contrast, antiestrogen tamoxifen decreases tumor angiogenesis in ER-positive breast cancer
(58–60).
Metastasis to distal organs is a major cause of death in cancer. In general, the E2-ERα path-
way does not stimulate tumor metastasis. ER-positive breast cancers have less metastasis potential
compared with more invasive ER-negative breast cancers. In addition, ER-positive breast cancer
patients often have a better prognosis than do ER-negative breast cancer patients. Epithelial-
mesenchymal transition is now considered the first step in metastasis. E2-ERα signaling up-
regulates epithelium-related transcription factors such as GATA3 and FOXA1 and promotes
mammary epithelial differentiation along the luminal/epithelial lineage (61). Estrogen signaling
inhibits de novo synthesis of RelB, a subunit of NF-κB that represses E-cadherin expression and
promotes cell migration and invasion (62). Moreover, forced expression of ERα in ERα-negative
breast cell lines induces the epithelial phenotype and reduces invasiveness, whereas knockdown
of ERα in ERα-positive breast cell lines leads to the mesenchymal phenotype and increased
invasiveness (63). Interestingly, the upregulation of several ER coregulators, such as AIB1 (am-
plified in breast cancer 1), SRC-1, and PELP1 (proline, glutamate, and leucine-rich protein 1),
promotes breast cancer invasiveness and metastasis (64). For example, AIB1 is encoded by a
well-known oncogene that is often overexpressed in breast cancer. In addition to stimulating cell
proliferation, AIB1 stimulates tumor cell motility and invasion. The Drosophila AIB1 homolog

is crucial for ovarian border cell migration and invasion during oogenesis (65). Elevated AIB1
expression is significantly correlated with seminal vesicle invasion and lymph node metastasis of
prostate cancer (66). AIB1 directly regulates the transcription of matrix metalloproteinase (MMP)-
SERMs: selective
estrogen receptor 2 and MMP-13 through its coactivation of AP1 and PEA3/ETV4 (ETS translocation variant 4)
modulators (66). AIB1 can promote cancer cell motility while remodeling the local microenvironment to
facilitate tumor cell invasion into the adjacent microenvironment (67). Instead of interacting
directly with the estrogen-ER complex, AIB1 is thought to participate in other signaling trans-
duction pathways or to act as a coregulator of other transcription factors in promoting tumor
metastasis (64).
INTERFERING WITH ESTROGEN ACTION IN CANCER TREATMENT

Antiestrogen strategies remain the primary breast cancer treatment because at least 70% of breast
cancers are classified as ER-positive breast cancers. As such, modulation of estrogen signaling has
been a mainstay of breast cancer treatment for more than a century. Prior to the development
of antiestrogen therapies, surgical oophorectomy was the chosen method of eliminating estrogen
function in premenopausal breast cancer patients. Tamoxifen was introduced in the 1970s, fol-
lowed by the rapid development of selective estrogen receptor modulators (SERMs) and AI. With
the success of these antiestrogen drugs, the American Society of Clinical Oncology no longer
recommends ovarian ablation in systematic breast cancer therapy (68).
SERMs are a group of synthetic chemical compounds that are structurally related to estro-
gens and that bind to and modulate ER function in different tissues (2). The FDA has approved
three SERMs: raloxifene, toremifene, and tamoxifen (Figure 1a). Raloxifene, a second-generation
SERM, is used mainly to treat or prevent osteoporosis. Toremifene has antiestrogenic activity in
the mammary gland. It is presently used in postmenopausal women with metastatic breast cancer
(69). In 2009, the FDA approved toremifene to reduce fractures in men who had prostate cancer
and who were receiving androgen deprivation therapy.
Fulvestrant is representative of yet another type of ER modulator that promotes ER turnover
in cells (70, 71). Fulvestrant has been approved as a third-line treatment for ER-positive metastatic
breast cancer in postmenopausal women.
Tamoxifen was the first drug developed to target ER function and, due to its efficacy and
low price, remains the preferred choice for treating hormone-sensitive breast cancers. Although
tamoxifen was initially used only in the treatment of advanced breast cancer in postmenopausal
women, it is now used as an adjuvant therapy to reduce the risk of breast cancer recurrence
after surgery in both pre- and postmenopausal women, as well as in women at high risk for
breast cancer. A large STAR (Study of Tamoxifen and Raloxifene) clinical study compared the
efficacies of tamoxifen and raloxifene in reducing the incidence of breast cancer. Finished in 2006,
STAR concluded that raloxifene is as effective as tamoxifen, although there were statistically
insignificantly fewer uterine cancers and blood clots in women taking raloxifene (72). Tamoxifen
greatly reduces the rate of breast cancer recurrence and has contributed significantly to the 25–30%
decrease in breast cancer mortality in the past two decades (73).
Tamoxifen acts as an ER antagonist in breast cancer cells. Crystal structure studies indicate
that the ER LBD interaction surfaces are composed of amino acid residues belonging to α-helices
3, 4, 5, and 12. When the ERα LBD is complexed with E2, α-helix 12 is positioned over the
ligand-binding pocket and forms an interaction surface for the recruitment of coactivators. In
contrast, when either the ERα LBD or the ERβ LBD is liganded with tamoxifen or raloxifene,
α-helix 12 is displaced from its agonist position and occupies the hydrophobic groove formed by
α-helices 3, 4, and 5, causing α-helix 12 to block the coactivator interaction surface (2, 74). Despite
232 Liang · Shang

acting as an ER antagonist in the breast, tamoxifen displays partial estrogenic effects in other target
tissues, such as the bone, uterus, and cardiovascular system. These partial estrogenic actions have
beneficial effects on the bone and the cardiovascular system in postmenopausal women. However,
Endocrine
tamoxifen has been associated with an increased incidence of endometrial cancer. Differential resistance:
expression of ER coregulators may contribute to the tissue-specific response to tamoxifen (75). failure to respond to
Comparison of gene expression profiles in cancerous versus normal endometrial epithelial cells antiestrogen therapy
treated with tamoxifen indicates that PAX2, one of the PAX family of transcription factors, is in the treatment of
breast cancer
the key player in tamoxifen-stimulated endometrial cancer (76). Finally, because ERβ does not
stimulate breast or uterine tissues in response to E2, selective ERβ agonists may be beneficial in Epigenetics: the
manifestation of a
treating breast cancer (16, 17).
phenotype, via changes
Breast cancer tissues express aromatase and produce higher levels of estrogen than do non- in chromatin states,
cancerous cells (7). Because aromatase catalyzes the final and rate-limiting step in estrogen biosyn- that can be transmitted
thesis, inhibitors of this enzyme are an effective targeted therapy for breast cancer. As discussed to the next generation
above, AIs are used mainly to treat breast cancer in postmenopausal women. AIs have also been of cells or individual
without altering the

combined with radiation therapy and/or chemotherapy to treat recurrent, metastatic, and high-
underlying DNA
risk endometrial cancer. There are two types of AIs. Type I inhibitors have a steroid-like structure
sequence (genotype)
similar to that of androstenedione, the substrate of aromatase, and the covalent binding between
these inhibitors and aromatase irreversibly inhibits the enzyme. In the case of type II inhibitors (or
nonsteroidal AIs), binding between the inhibitors and aromatase is noncovalent, and androgen can
compete with these agents and relieve the inhibitory effect on aromatase function. Three AIs—
anastrozole, letrozole, and exemestane—are FDA approved and used in clinical practice. Among
these agents, exemestane is a type I inhibitor, and anastrozole and letrozole are type II inhibitors.
AIs can be used after five years of tamoxifen treatment, as recommended by the National Compre-
hensive Cancer Network breast cancer guidelines. AIs are often effective in tamoxifen-resistant
breast cancer (7) because AIs reduce estrogen biosynthesis, whereas tamoxifen antagonizes estro-
gen action within breast cancer cells.
EPIGENETICS AND ENDOCRINE RESISTANCE IN CANCER

Although antiestrogen drugs have proven to be the most successful targeted cancer therapy in
modern medicine, drug resistance remains a major challenge in the treatment of breast cancer,
even with positive ER expression. The National Cancer Institute estimates that more than 200,000
Americans are diagnosed with breast cancer every year. More than 65% of breast tumors express
ERα, but fewer than half of those tumors respond to antiestrogen therapy (77). Moreover, a
significant number of patients who initially respond to antiestrogen agents eventually become
refractory and exhibit a more aggressive disease with a poorer prognosis. Numerous studies have
tried to elucidate the underlying mechanisms of both intrinsic and acquired endocrine resistance,
and various approaches have been proposed to enhance the antitumor efficacy of tamoxifen and AIs.
Fighting endocrine resistance remains a significant challenge in the field of breast cancer research.
Recently, several comprehensive reviews have focused on the possible underlying mechanisms of
endocrine resistance in breast cancer (19, 28, 78). Most research in this area has focused on
tamoxifen resistance, given its widespread use and the existence of tamoxifen-resistant cell lines
and animal models for mechanistic studies.
In general, resistance to antiestrogen therapy can be caused by genetic or epigenetic deregula-
tion of all components in the estrogen signaling pathway. The prodrug tamoxifen is first converted
to its active metabolite, endoxifen, by the hepatic drug-metabolizing enzyme cytochrome P450
2D6 (CYP2D6). Polymorphisms in the CYP2D6 gene alter the efficiency of the tamoxifen-to-
endoxifen conversion and can greatly affect the clinical response to tamoxifen. Although a strong

link between CYP2D6 polymorphisms and tamoxifen response is unestablished, genetic screening
for CYP2D6 variants may eventually prove useful for guiding the selection and dose of tamoxifen
(79).
DNMT: DNA
methyltransferase Ligand binding to ER recruits a panel of coactivators or corepressors; variation in coregulator
expression greatly affects the composition and output of the large ligand-ER complex. Conse-
HDAC: histone
deacetylase quently, abnormal expression of ER coregulators, such as AIB1 and SRC-1, or of components of
other signaling pathways, such as ERBB2, can contribute to tamoxifen resistance (19, 80). Genetic
mutation, gene amplification, gene fusion, and epigenetic deregulations can alter the expression of
coregulators. For example, both AIB1 overexpression by gene amplification and certain AIB1 poly-
morphisms cause tamoxifen resistance in patients (67, 81). Overexpression of the specific splicing
variant AIB3 can also affect responsiveness to antiestrogen therapy because this variant appears
to be more potent than wild-type AIB1 in provoking in vivo pathological changes in the mammary
gland (67). Dysregulation of these ER targets is thought to oppose the antagonistic effects of tamox-
ifen and to contribute to drug resistance. For example, overexpression of cyclin D1 or underexpres-
sion of Bcl-2 is associated with many tamoxifen-resistant breast cancer patients (19). Large-scale
genomic studies have identified gene signatures that predict therapeutic responses to endocrine
therapies, albeit with inconsistent results (19). In addition, noncoding RNAs such as miR-451 may
also play a role in tamoxifen resistance (82, 83). The studies suggest that targeting specific genes
associated with resistance may increase the efficacy of tamoxifen, as shown for trastuzumab, an anti-
ERBB2 drug used as an adjuvant therapy in ER-positive, ERBB2-positive breast cancer (19, 28).
Efforts to define epigenetic mechanisms underlying endocrine resistance have been made (80,
84). Tamoxifen resistance emerges two to three years after the initial drug administration. This
time factor suggests that defects in epigenetic marks, rather than primary DNA mutations, likely
play a role in the progression of drug resistance. Epigenetic events can impact chromatin by di-
rect DNA methylation at cytosine on CpG sequences, PTMs of histones, and the presence of
histone variants and nonhistone chromosomal proteins. All these epigenetic factors greatly in-
fluence local gene expression, and the reversibility of epigenetic modifications also makes them
druggable. Environmental cues influence epigenetic regulation, and it is tempting to speculate
that long-term treatment with tamoxifen or other antiestrogen agents may induce epigenetic
changes in breast cancer and endometrial cancer cells. Epigenetic factors may also contribute
to endocrine resistance in breast cancer, with loss of ER expression attributed to promoter hy-
permethylation of the ESR1 promoter (16). Treating ER-negative breast cancer cells with the
DNA methyltransferase (DNMT) inhibitor AZA restores ER expression and sensitizes these cells
to tamoxifen treatment (85). ESR1 is not the only gene that is subjected to abnormal methyla-
tion in tamoxifen-resistant breast cancer cells. Candidate gene and unbiased approaches using
high-throughput DNA methylation profiling revealed different promoter methylation signatures
predictive of tamoxifen responsiveness (85, 86). Unfortunately, other than PITX2 (paired-like
homeodomain 2), a consensus of relevant markers affected by methylation has yet to emerge. In
this respect, DNA methylation mapping by whole-genome bisulfite sequencing may be useful in
identifying the relevant markers of endocrine resistance.
Although histone modifications also affect global or individual gene expression, less is known
about how abnormal histone modifications contribute to endocrine resistance in breast cancer.
Lysine acetylation of histone H3 and H4 often leads to an open chromatin structure and there-
fore correlates with transcriptional activation. Histone acetylation is catalyzed by HATs and is
removed by histone deacetylases (HDACs). Mutations or abnormal expression of several HATs,
such as CBP, p300, and Hbo1, or of HDACs, such as HDAC1, HDAC2, HDAC3, and HDAC6,
are associated with breast cancer progression or prognosis (85, 87). Histone lysine methylation
can cause either transcriptional activation or transcriptional repression, depending on the specific
234 Liang · Shang

residue and methylation state (mono-, di-, or trimethylation). The methyltransferase EZH2 cat-
alyzes trimethylation of H3K27, and overexpression of EZH2 has a significant correlation with
advanced stages and poor prognosis of many types of cancer, including that of the breast. Ex-
pression of other histone methyltransferases or demethylases is often altered in different stages of
breast cancer (80, 87); such expression presumably affects global or local chromatin, alters gene
expression, and ultimately leads to tumor progression or drug resistance.
Although the underlying mechanisms for deregulated histone modifications in endocrine resis-
tance have yet to be defined, many laboratory and clinical studies have evaluated specific enzyme
inhibitors in breast cancer treatment. Combining AZA and the HDAC inhibitor TSA can greatly
restore ERα expression and sensitize ER-negative breast cancer cells to tamoxifen treatment (88).
A recent study demonstrates that addition of the HDAC inhibitor vorinostat (VPA) to ER-positive
breast cancer cells changes the normal response to tamoxifen from growth arrest to apoptotic cell
death. Thus, HDAC inhibitors may increase the efficacy of tamoxifen treatment (77). In this re-
gard, the FDA has approved VPA for the treatment of cutaneous T cell lymphoma, and at least 80
trials are under way to assess the clinical usefulness of other HDAC inhibitors in hematological
and solid malignancies.
FUTURE PERSPECTIVES
Theoretically, any cell that expresses ER could respond to estrogen and other ER modulators.
Sustained estrogen exposure or deregulated estrogen signaling is associated with many types of
cancer, including those of the breast, endometrium, ovary, prostate, lung, and colon. Although
tamoxifen and AIs have been used mainly to treat breast cancer and certain types of endometrial
cancer, we do not yet know whether these antiestrogen therapies could be used to treat other
cancers. A recent report indicates that E2 stimulates ER-positive lung adenocarcinoma cell growth
but inhibits ER-negative lung adenocarcinoma cell growth (89). Whether interfering with estrogen
signaling benefits ER-positive lung cancer patients remains to be determined. Developing new
ERα-specific SERMs is still one of the major strategies for treating tamoxifen-resistant breast
cancer and other estrogen-related diseases. Increasing evidence indicates that changing the ratio
of ERα/ERβ expression may play a pivotal role in tumor development and progression. Given that
ERβ acts as a tumor suppressor to inhibit cell proliferation, cell growth, and angiogenesis, an ERβ
agonist could benefit ERβ-positive cancer patients. Future efforts to target ERβ offer an alternative
approach to finding new ERα-specific SERMs. Finally, identifying global gene signatures that
predict the antiestrogen responsiveness of specific tissues could better guide clinical applications
of single and combined drug therapies in the fight against estrogen-responsive cancers.
SUMMARY POINTS
1. Estrogen is a well-established risk factor for many types of cancer, particularly breast and
endometrial cancer.
2. The primary mediators of estrogen action are estrogen receptor (ER)α and ERβ, which
function as ligand-induced transcription factors to regulate the expression of diverse
genes.
3. The oncogenic effects of estrogen are due mainly to ERα-mediated transcriptional acti-
vation of genes that promote cell proliferation or alleviate apoptosis.

4. Selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are the
two main antiestrogen therapies.
5. Epigenetic factors contribute greatly to endocrine resistance in breast cancer treatment.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
Research in our lab was supported by grants (81130048 and 30921062 to Y.S.) from the National
Natural Science Foundation of China and grants (973 Program: 2011CB504204 to J.L. and Y.S.)
from the Ministry of Science and Technology of China.
LITERATURE CITED
1. Koos RD. 2011. Minireview: putting physiology back into estrogens’ mechanism of action. Endocrinology
152:4481–88
2. Shang Y. 2006. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat. Rev.
Cancer 6:360–68
3. Shang Y. 2007. Hormones and cancer. Cell Res. 17:277–79
4. Prentice RL, Anderson GL. 2008. The women’s health initiative: lessons learned. Annu. Rev. Public Health
29:131–50
5. Auchus ML, Auchus RJ. 2012. Human steroid biosynthesis for the oncologist. J. Investig. Med. 60:495–
503
6. Miller WL, Auchus RJ. 2011. The molecular biology, biochemistry, and physiology of human steroido-
genesis and its disorders. Endocr. Rev. 32:81–151
7. Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. 2011. Aromatase, aromatase inhibitors, and breast
cancer. J. Steroid Biochem. Mol. Biol. 125:13–22
8. Brueggemeier RW. 2001. Aromatase, aromatase inhibitors, and breast cancer. Am. J. Ther. 8:333–
44
9. Cleary MP, Grossmann ME. 2009. Minireview: obesity and breast cancer: the estrogen connection.
Endocrinology 150:2537–42
10. Wibowo E, Schellhammer P, Wassersug RJ. 2011. Role of estrogen in normal male function: clinical
implications for patients with prostate cancer on androgen deprivation therapy. J. Urol. 185:17–23
11. Folkerd EJ, Dowsett M. 2010. Influence of sex hormones on cancer progression. J. Clin. Oncol. 28:4038–
44
12. Jensen EV, Jacobson HI, Walf AA, Frye CA. 2010. Estrogen action: a historic perspective on the impli-
cations of considering alternative approaches. Physiol. Behav. 99:151–62
13. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, et al. 2007. Estrogen receptors: How do they
signal and what are their targets. Physiol. Rev. 87:905–31
14. Bjornstrom L, Sjoberg M. 2005. Mechanisms of estrogen receptor signaling: convergence of genomic and
nongenomic actions on target genes. Mol. Endocrinol. 19:833–42
15. Hammes SR, Levin ER. 2011. Minireview: recent advances in extranuclear steroid receptor actions.
Endocrinology 152:4489–95
16. Thomas C, Gustafsson JA. 2011. The different roles of ER subtypes in cancer biology and therapy. Nat.
Rev. Cancer 11:597–608
236 Liang · Shang

17. Nilsson S, Koehler KF, Gustafsson JA. 2011. Development of subtype-selective oestrogen receptor-based
therapeutics. Nat. Rev. Drug Discov. 10:778–92
18. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. 1996. Cloning of a novel receptor
expressed in rat prostate and ovary. Proc. Natl. Acad. Sci. USA 93:5925–30
19. Musgrove EA, Sutherland RL. 2009. Biological determinants of endocrine resistance in breast cancer.
Nat. Rev. Cancer 9:631–43
20. Leong H, Riby JE, Firestone GL, Bjeldanes LF. 2004. Potent ligand-independent estrogen receptor
activation by 3,3 -diindolylmethane is mediated by cross talk between the protein kinase A and mitogen-
activated protein kinase signaling pathways. Mol. Endocrinol. 18:291–302
21. Stender JD, Kim K, Charn TH, Komm B, Chang KC, et al. 2010. Genome-wide analysis of estro-
gen receptor α DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in
receptor-mediated transcriptional activation. Mol. Cell. Biol. 30:3943–55
22. Jerry DJ, Dunphy KA, Hagen MJ. 2010. Estrogens, regulation of p53 and breast cancer risk: a balancing
act. Cell. Mol. Life Sci. 67:1017–23
23. Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. 2000. Effect of single and compound
knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes. Development
127:4277–91
24. Imamov O, Lopatkin NA, Gustafsson JA. 2004. Estrogen receptor β in prostate cancer. N. Engl. J. Med.
351:2773–74
25. Forster C, Makela S, Warri A, Kietz S, Becker D, et al. 2002. Involvement of estrogen receptor β in
terminal differentiation of mammary gland epithelium. Proc. Natl. Acad. Sci. USA 99:15578–83
26. Antal MC, Krust A, Chambon P, Mark M. 2008. Sterility and absence of histopathological defects in
nonreproductive organs of a mouse ERβ-null mutant. Proc. Natl. Acad. Sci. USA 105:2433–38
27. Wang Z, Zhang X, Shen P, Loggie BW, Chang Y, Deuel TF. 2005. Identification, cloning, and expression
of human estrogen receptor-α36, a novel variant of human estrogen receptor-α66. Biochem. Biophys. Res.
Commun. 336:1023–27
28. Jordan VC, O’Malley BW. 2007. Selective estrogen-receptor modulators and antihormonal resistance in
breast cancer. J. Clin. Oncol. 25:5815–24
29. Li S, Shang Y. 2007. Regulation of SRC family coactivators by post-translational modifications.
Cell. Signal. 19:1101–12
30. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, et al. 1997. Steroid receptor coactivator-1 is a
histone acetyltransferase. Nature 389:194–98
31. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, et al. 1997. Nuclear receptor coactivator ACTR is
a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300.
Cell 90:569–80
32. Liang J, Zhang H, Zhang Y, Zhang Y, Shang Y. 2009. GAS, a new glutamate-rich protein, interacts
differentially with SRCs and is involved in oestrogen receptor function. EMBO Rep. 10:51–57
33. Tsai HW, Katzenellenbogen JA, Katzenellenbogen BS, Shupnik MA. 2004. Protein kinase A activation
of estrogen receptor α transcription does not require proteasome activity and protects the receptor from
ligand-mediated degradation. Endocrinology 145:2730–38
34. Bunone G, Briand PA, Miksicek RJ, Picard D. 1996. Activation of the unliganded estrogen receptor by
EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J. 15:2174–83
35. Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, et al. 2001. Direct acetylation of the
estrogen receptor α hinge region by p300 regulates transactivation and hormone sensitivity. J. Biol.
Chem. 276:18375–83
36. Berry NB, Fan M, Nephew KP. 2008. Estrogen receptor-α hinge-region lysines 302 and 303 regulate
receptor degradation by the proteasome. Mol. Endocrinol. 22:1535–51
37. Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L. 2011. Cracking the estrogen
receptor’s posttranslational code in breast tumors. Endocr. Rev. 32:597–622
38. Chen D, Ma H, Hong H, Koh SS, Huang SM, et al. 1999. Regulation of transcription by a protein
methyltransferase. Science 284:2174–77
39. Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, et al. 2001. Methylation of histone H3 by coactivator-
associated arginine methyltransferase 1. Biochemistry 40:5747–56

40. Chevillard-Briet M, Trouche D, Vandel L. 2002. Control of CBP co-activating activity by arginine
methylation. EMBO J. 21:5457–66
41. Naeem H, Cheng D, Zhao Q, Underhill C, Tini M, et al. 2007. The activity and stability of the tran-
scriptional coactivator p/CIP/SRC-3 are regulated by CARM1-dependent methylation. Mol. Cell. Biol.
27:120–34
42. Sims RJ 3rd, Rojas LA, Beck D, Bonasio R, Schuller R, et al. 2011. The C-terminal domain of RNA
polymerase II is modified by site-specific methylation. Science 332:99–103
43. Carascossa S, Dudek P, Cenni B, Briand PA, Picard D. 2010. CARM1 mediates the ligand-independent
and tamoxifen-resistant activation of the estrogen receptor α by cAMP. Genes Dev. 24:708–19
44. Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. 2000. Cofactor dynamics and sufficiency in estrogen
receptor-regulated transcription. Cell 103:843–52
45. Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, et al. 2006. Genome-wide analysis of estrogen
receptor binding sites. Nat. Genet. 38:1289–97
46. Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, et al. 2005. Chromosome-wide mapping of estro-
gen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122:33–
43
47. Fullwood MJ, Liu MH, Pan YF, Liu J, Xu H, et al. 2009. An oestrogen-receptor-α-bound human chro-
matin interactome. Nature 462:58–64

48. Zhao C, Putnik M, Gustafsson J-Å, Dahlman-Wright K. 2009. Microarray analysis of altered gene ex-
pression in ERβ-overexpressing HEK293 cells. Endocrine 36:224–32
49. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. 2011. Cyclin D as a therapeutic target
in cancer. Nat. Rev. Cancer 11:558–72
50. Caldon CE, Sutherland RL, Musgrove E. 2010. Cell cycle proteins in epithelial cell differentiation:
implications for breast cancer. Cell Cycle 9:1918–28
51. Butt AJ, McNeil CM, Musgrove EA, Sutherland RL. 2005. Downstream targets of growth factor and
oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E.
Endocr. Relat. Cancer 12(Suppl. 1):47–59
52. Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, et al. 2011. Estrogen induces c-myc gene expression
via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol.
Endocrinol. 25:1527–38
53. Strom A, Hartman J, Foster JS, Kietz S, Wimalasena J, Gustafsson JA. 2004. Estrogen receptor β inhibits
17β-estradiol-stimulated proliferation of the breast cancer cell line T47D. Proc. Natl. Acad. Sci. USA
101:1566–71
54. Gompel A, Somai S, Chaouat M, Kazem A, Kloosterboer HJ, et al. 2000. Hormonal regulation of apoptosis
in breast cells and tissues. Steroids 65:593–98
55. Ariazi EA, Cunliffe HE, Lewis-Wambi JS, Slifker MJ, Willis AL, et al. 2011. Estrogen induces apopto-
sis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene
expression across time. Proc. Natl. Acad. Sci. USA 108:18879–86
56. Lewis-Wambi JS, Jordan VC. 2009. Estrogen regulation of apoptosis: How can one hormone stimulate
and inhibit? Breast Cancer Res. 11:206
57. Vasconsuelo A, Pronsato L, Ronda AC, Boland R, Milanesi L. 2011. Role of 17β-estradiol and testosterone
in apoptosis. Steroids 76:1223–31
58. Miller VM, Duckles SP. 2008. Vascular actions of estrogens: functional implications. Pharmacol. Rev.
60:210–41
59. Bendrik C, Dabrosin C. 2009. Estradiol increases IL-8 secretion of normal human breast tissue and breast
cancer in vivo. J. Immunol. 182:371–78
60. Lindahl G, Saarinen N, Abrahamsson A, Dabrosin C. 2012. Tamoxifen, flaxseed, and the lignan entero-
lactone increase stroma- and cancer cell-derived IL-1Ra and decrease tumor angiogenesis in estrogen-
dependent breast cancer. Cancer Res. 71:51–60
61. McCune K, Mehta R, Thorat MA, Badve S, Nakshatri H. 2010. Loss of ERα and FOXA1 expression in
a progression model of luminal type breast cancer: insights from PyMT transgenic mouse model. Oncol.
Rep. 24:1233–39
238 Liang · Shang

62. Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, et al. 2007. Oestrogen signalling inhibits
invasive phenotype by repressing RelB and its target BCL2. Nat. Cell Biol. 9:470–78
63. Guttilla IK, Adams BD, White BA. 2012. ERα, microRNAs, and the epithelial-mesenchymal transition
in breast cancer. Trends Endocrinol. Metab. 23:73–82
64. Saha Roy S, Vadlamudi RK. 2012. Role of estrogen receptor signaling in breast cancer metastasis. Int. J.
Breast Cancer 2012:654698
65. Bai J, Uehara Y, Montell DJ. 2000. Regulation of invasive cell behavior by taiman, a Drosophila protein
related to AIB1, a steroid receptor coactivator amplified in breast cancer. Cell 103:1047–58
66. Yan J, Erdem H, Li R, Cai Y, Ayala G, et al. 2008. Steroid receptor coactivator-3/AIB1 promotes cell
migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression.
Cancer Res. 68:5460–68
67. Lydon JP, O’Malley BW. 2011. Minireview: steroid receptor coactivator-3: a multifarious coregulator in
mammary gland metastasis. Endocrinology 152:19–25
68. Griggs JJ, Somerfield MR, Anderson H, Henry NL, Hudis CA, et al. 2011. American Society of Clinical
Oncology endorsement of the cancer care Ontario practice guideline on adjuvant ovarian ablation in
the treatment of premenopausal women with early-stage invasive breast cancer. J. Clin. Oncol. 29:3939–
42
69. Zhou WB, Ding Q, Chen L, Liu XA, Wang S. 2011. Toremifene is an effective and safe alternative to
tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials. Breast Cancer
Res. Treat. 128:625–31
70. Wardell SE, Marks JR, McDonnell DP. 2011. The turnover of estrogen receptor α by the selective
estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist
efficacy. Biochem. Pharmacol. 82:122–30
71. Wittmann BM, Sherk A, McDonnell DP. 2007. Definition of functionally important mechanistic differ-
ences among selective estrogen receptor down-regulators. Cancer Res. 67:9549–60
72. 2006. STAR trial reports. Eur. J. Cancer 42:1694
73. McDonnell DP, Wardell SE. 2010. The molecular mechanisms underlying the pharmacological actions
of ER modulators: implications for new drug discovery in breast cancer. Curr. Opin. Pharmacol. 10:620–
28
74. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, et al. 1998. The structural basis of estro-
gen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95:927–
37
75. Shang Y, Brown M. 2002. Molecular determinants for the tissue specificity of SERMs. Science 295:2465–68
76. Wu H, Chen Y, Liang J, Shi B, Wu G, et al. 2005. Hypomethylation-linked activation of PAX2 mediates
tamoxifen-stimulated endometrial carcinogenesis. Nature 438:981–87
77. Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN. 2011. Addition of a histone deacetylase
inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction
of autophagy. Breast Cancer Res. Treat. 130:437–47
78. Jordan VC. 2007. New insights into the metabolism of tamoxifen and its role in the treatment and
prevention of breast cancer. Steroids 72:829–42
79. Hoskins JM, Carey LA, McLeod HL. 2009. CYP2D6 and tamoxifen: DNA matters in breast cancer.
Nat. Rev. Cancer 9:576–86
80. Green KA, Carroll JS. 2007. Oestrogen-receptor-mediated transcription and the influence of co-factors
and chromatin state. Nat. Rev. Cancer 7:713–22
81. Burwinkel B, Wirtenberger M, Klaes R, Schmutzler RK, Grzybowska E, et al. 2005. Association of
NCOA3 polymorphisms with breast cancer risk. Clin. Cancer Res. 11:2169–74
82. Bergamaschi A, Katzenellenbogen BS. 2012. Tamoxifen downregulation of miR-451 increases 14-3-3ζ
and promotes breast cancer cell survival and endocrine resistance. Oncogene 31:39–47
83. Veeck J, Esteller M. 2010. Breast cancer epigenetics: from DNA methylation to microRNAs. J. Mammary
Gland Biol. Neoplasia 15:5–17
84. Kelly TK, De Carvalho DD, Jones PA. 2010. Epigenetic modifications as therapeutic targets.
Nat. Biotechnol. 28:1069–78

85. Pathiraja TN, Stearns V, Oesterreich S. 2010. Epigenetic regulation in estrogen receptor positive breast
cancer—role in treatment response. J. Mammary Gland Biol. Neoplasia 15:35–47
86. Reis-Filho JS, Pusztai L. 2011. Gene expression profiling in breast cancer: classification, prognostication,
and prediction. Lancet 378:1812–23
87. Dalvai M, Bystricky K. 2010. The role of histone modifications and variants in regulating gene expression
in breast cancer. J. Mammary Gland Biol. Neoplasia 15:19–33
88. Badia E, Oliva J, Balaguer P, Cavailles V. 2007. Tamoxifen resistance and epigenetic modifications in
breast cancer cell lines. Curr. Med. Chem. 14:3035–45
89. Lin S, Lin CJ, Hsieh DP, Li LA. 2012. ERα phenotype, estrogen level, and benzo[a]pyrene exposure
modulate tumor growth and metabolism of lung adenocarcinoma cells. Lung Cancer 75:285–92
240 Liang · Shang

PH75-FrontMatter ARI 15 January 2013 20:3
Annual Review of
Physiology
Volume 75, 2013 Contents

PERSPECTIVES, David Julius, Editor

A Conversation with Roger Guillemin

Roger Guillemin and Greg Lemke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
CARDIOVASCULAR PHYSIOLOGY, Marlene Rabinovitch, Section Editor

The Adventitia: Essential Regulator of Vascular Wall Structure
and Function
Kurt R. Stenmark, Michael E. Yeager, Karim C. El Kasmi,
Eva Nozik-Grayck, Evgenia V. Gerasimovskaya, Min Li, Suzette R. Riddle,
and Maria G. Frid p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23
Coping with Endoplasmic Reticulum Stress in the
Cardiovascular System
Jody Groenendyk, Luis B. Agellon, and Marek Michalak p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Functions of MicroRNAs in Cardiovascular Biology and Disease
Akiko Hata p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p69
Mitochondria in Vascular Health and Disease
Peter Dromparis and Evangelos D. Michelakis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95
CELL PHYSIOLOGY, David E. Clapham, Section Editor

Mammalian Phospholipase C
Ganesh Kadamur and Elliott M. Ross p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 127
Regulation of Insulin Secretion in Human Pancreatic Islets
Patrik Rorsman and Matthias Braun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 155
TRPA1: A Gatekeeper for Inflammation
Diana M. Bautista, Maurizio Pellegrino, and Makoto Tsunozaki p p p p p p p p p p p p p p p p p p p p p p 181
vi
ENDOCRINOLOGY, Holly A. Ingraham, Section Editor

The Androgen Receptor in Health and Disease
Takahiro Matsumoto, Matomo Sakari, Maiko Okada, Atsushi Yokoyama,
Sayuri Takahashi, Alexander Kouzmenko, and Shigeaki Kato p p p p p p p p p p p p p p p p p p p p p p p p 201
Estrogen and Cancer
Jing Liang and Yongfeng Shang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225
GASTROINTESTINAL PHYSIOLOGY, Linda Samuelson, Section Editor

Autophagy and Intestinal Homeostasis
Khushbu K. Patel and Thaddeus S. Stappenbeck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 241
Notch in the Intestine: Regulation of Homeostasis and Pathogenesis
Taeko K. Noah and Noah F. Shroyer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 263

Paneth Cells: Maestros of the Small Intestinal Crypts

Hans C. Clevers and Charles L. Bevins p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 289
NEUROPHYSIOLOGY, Roger Nicoll, Section Editor

Functional Insights from Glutamate Receptor Ion Channel Structures
Janesh Kumar and Mark L. Mayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 313
The Impact of Adult Neurogenesis on Olfactory Bulb Circuits
and Computations
Gabriel Lepousez, Matthew T. Valley, and Pierre-Marie Lledo p p p p p p p p p p p p p p p p p p p p p p p p p 339
Pathophysiology of Migraine
Daniela Pietrobon and Michael A. Moskowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 365
Perspectives on Kiss-and-Run: Role in Exocytosis, Endocytosis,
and Neurotransmission
AbdulRasheed A. Alabi and Richard W. Tsien p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 393
Understanding the Rhythm of Breathing: So Near, Yet So Far
Jack L. Feldman, Christopher A. Del Negro, and Paul A. Gray p p p p p p p p p p p p p p p p p p p p p p p p 423
RENAL AND ELECTROLYTE PHYSIOLOGY, Peter Aronson, Section Editor

Chloride in Vesicular Trafficking and Function
Tobias Stauber and Thomas J. Jentsch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 453
Claudins and the Kidney
Jianghui Hou, Madhumitha Rajagopal, and Alan S.L. Yu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479
Fibroblast Growth Factor 23 and Klotho: Physiology and
Pathophysiology of an Endocrine Network of Mineral Metabolism
Ming Chang Hu, Kazuhiro Shiizaki, Makoto Kuro-o, and Orson W. Moe p p p p p p p p p p p p 503
vii
Phosphate Transporters and Their Function

Jürg Biber, Nati Hernando, and Ian Forster p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 535
RESPIRATORY PHYSIOLOGY, Augustine M.K. Choi, Section Editor

Claudin Heterogeneity and Control of Lung Tight Junctions
Michael Koval p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 551
Platelets in Lung Biology
Andrew S. Weyrich and Guy A. Zimmerman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 569
Regulation and Repair of the Alveolar-Capillary Barrier in Acute
Lung Injury
Jahar Bhattacharya and Michael A. Matthay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 593
SPECIAL TOPIC, AGING AND LONGEVITY, Thomas A. Rando, Section Editor

The Ins and Outs of Aging and Longevity

Thomas A. Rando p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 617
Genetics of Longevity in Model Organisms: Debates
and Paradigm Shifts
David Gems and Linda Partridge p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 621
Genome Instability and Aging
Jan Vijg and Yousin Suh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 645
Metabolic and Neuropsychiatric Effects of Calorie Restriction
and Sirtuins
Sergiy Libert and Leonard Guarente p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 669
Aging, Cellular Senescence, and Cancer
Judith Campisi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 685
Indexes
Cumulative Index of Contributing Authors, Volumes 71–75 p p p p p p p p p p p p p p p p p p p p p p p p p p p 707

Cumulative Index of Article Titles, Volumes 71–75 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 710
Errata
An online log of corrections to Annual Review of Physiology articles may be found at

http://physiol.annualreviews.org/errata.shtml
viii

Estrogen and Cancer

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Estrogen and Cancer

Uploaded by

Copyright:

Available Formats

Estrogen and Cancer

Jing Liang1,2 and Yongfeng Shang1,2,∗

Annu. Rev. Physiol. 2013. 75:225–40 Keywords

The Annual Review of Physiology is online at Abstract

ESTROGEN METABOLISM IN NORMAL AND CANCER CELLS

226 Liang · Shang

Tamoxifen Toremifene Raloxifene

b AF-1 DBD LBD

MOLECULAR MECHANISMS OF ESTROGEN ACTION

www.annualreviews.org • Estrogen and Cancer 227

228 Liang · Shang

www.annualreviews.org • Estrogen and Cancer 229

ESTROGEN SIGNALING IN CARCINOGENESIS

230 Liang · Shang

acute, inhibitory effect. Inhibition of c-Myc or cyclin D1 activity abrogates estrogen-stimulated

www.annualreviews.org • Estrogen and Cancer 231

INTERFERING WITH ESTROGEN ACTION IN CANCER TREATMENT

232 Liang · Shang

without altering the

EPIGENETICS AND ENDOCRINE RESISTANCE IN CANCER

www.annualreviews.org • Estrogen and Cancer 233

234 Liang · Shang

www.annualreviews.org • Estrogen and Cancer 235

236 Liang · Shang

www.annualreviews.org • Estrogen and Cancer 237

matin interactome. Nature 462:58–64

238 Liang · Shang

www.annualreviews.org • Estrogen and Cancer 239

240 Liang · Shang

Volume 75, 2013 Contents

PERSPECTIVES, David Julius, Editor

A Conversation with Roger Guillemin

CARDIOVASCULAR PHYSIOLOGY, Marlene Rabinovitch, Section Editor

CELL PHYSIOLOGY, David E. Clapham, Section Editor

ENDOCRINOLOGY, Holly A. Ingraham, Section Editor

GASTROINTESTINAL PHYSIOLOGY, Linda Samuelson, Section Editor

Taeko K. Noah and Noah F. Shroyer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 263

Paneth Cells: Maestros of the Small Intestinal Crypts

NEUROPHYSIOLOGY, Roger Nicoll, Section Editor

RENAL AND ELECTROLYTE PHYSIOLOGY, Peter Aronson, Section Editor

Phosphate Transporters and Their Function

RESPIRATORY PHYSIOLOGY, Augustine M.K. Choi, Section Editor

SPECIAL TOPIC, AGING AND LONGEVITY, Thomas A. Rando, Section Editor

The Ins and Outs of Aging and Longevity

Cumulative Index of Contributing Authors, Volumes 71–75 p p p p p p p p p p p p p p p p p p p p p p p p p p p 707

An online log of corrections to Annual Review of Physiology articles may be found at

You might also like