The biological role of estrogen receptors α and β in cancer
Introduction
Estradiol (E2) regulates the growth, differentiation, and physiology of the reproductive process through the estrogen receptor (ER). E2 also affects other tissues, such as bone, liver, brain and the cardiovascular system. Because of the functional diversity displayed by estrogens through the ER, much of the current interest in understanding the basis of ER actions at the molecular level is focused towards the goal of therapeutic intervention [1], [2].
One of the earliest studies reporting a relationship between breast cancer and ovarian hormones described breast tumor regression after removal of the ovaries [3], the major site of estrogen production in premenopausal women. However, only one in three women respond to oophorectomy [4]. The explanation for these observations became clear when the ER was discovered [5]. In the late 1960s and early 1970s, the ER was initially used as a predictor of breast cancer response to endocrine ablation. Tumors that were ER rich were more likely to respond to endocrine therapy than if the tumor was ER poor [6], [7]. In the mid 1970s, before adjuvant therapy became the standard of care, the ER was viewed as a prognostic indicator after surgery, with ER-positive patients responding better than ER negative patients [8]. From the 1970s to the present day, the ER has evolved to be the most effective target for breast cancer therapy. Interactions between E2 and the ER can be blocked using a variety of agents. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene, are competitive inhibitors of E2 at the ER and display agonist or antagonist behavior depending on the tissue [9]. Pure antiestrogens, exemplified by fulvestrant (ICI 182,780), only produce antagonist effects and are proving to be useful in treating advanced breast cancer [10], [11]. Aromatase inhibitors, such as anastrozole, that block the conversion of androstenedione or testosterone to estrone and estradiol, respectively, are a particularly interesting new approach to breast cancer treatment as the compounds appear to increase efficacy and reduce side effects compared with tamoxifen [12], [13], [14], [15]. The optimal combinations and sequential orders of treatment continue to be investigated in clinical trials.
Although the primary focus of research for the first 30 years (1960–1990) has been on the role of steroid receptors in reproductive functions and breast cancer, there is reason to believe that there are opportunities to design new molecules targeted to novel sites dominated by one ER or the other. This is especially true since the publication of the Women’s Health Initiative did not demonstrate an overall health benefit for women taking hormone replacement therapy (HRT) [16]. Positive aspects of HRT include a decrease in the rate of bone density loss, a decrease in total and LDL cholesterol, and a protective effect against colon cancer. However, the risk of breast cancer is increased in HRT users [17]. The challenge now is to dissect the individual roles of ERα and ERβ as transcription factors that participate in normal and abberant physiological processes. Clearly, the goal will be a menu of multifunctional medicines that can be used singly or in combination to treat and prevent a range of diseases associated with menopause or reproductive function.
Section snippets
Isoforms, domains, ligand binding characteristics and expression of ERα and ERβ
The therapeutic targets estrogen receptors α (ERα) and β (ERβ) are members of the nuclear receptor superfamily of transcription factors. Other members of this family include thyroid receptor, Vitamin D receptor, retinoic acid receptor, and other steroid receptors such as the glucocorticoid receptor, androgen receptor, progesterone receptor and mineralocorticoid receptor.
ERα was the first estrogen receptor cloned and it was isolated from MCF-7 human breast cancer cells in the late 1980s [18],
Transcriptional activity
The transcriptional activity of the ER is mediated by AF1 and AF2 (Fig. 1) [39], [40], [41], [42] and these regions were largely delineated using mutational studies. The activity of AF1 and AF2 differs depending on the cellular environment and promoter context [43]. In some cells, either AF1 or AF2 is dominant, and in others, both activation functions synergize [44]. In addition, AF1 and AF2 are differentially regulated by ligand. E2 is an agonist regardless of whether AF1 or AF2 is dominant.
Tissue distribution
Analysis of the tissue distribution of ERα and ERβ provides insight into the potential for targeting specific tissues. The relative distribution of ERα and ERβ mRNA was initially determined in rat tissues using RT-PCR [32]. ERα mRNA was highly expressed in epididymis, testis, pituitary gland, ovary, uterus, kidney and adrenal. Moderate amounts were also present in the prostate gland, bladder, liver, thymus and heart. Highest amounts of ERβ mRNA were detected in the prostate gland and ovary. In
The role of ERα and ERβ in cancer
The analysis of knockout mice has provided a framework in which to study the potential functions of ERα and ERβ in human target tissues. Phenotypes of αERKO mice have pointed toward the importance of ERα in the uterus and mammary gland of females. In addition, βERKO mice have suggested an important function for ERβ in the ovary in females and in the prostate gland in males. The laboratory studies in mice naturally advance the study of the complex role of the individual ERs in human cancer.
Current status of the ER and future research directions
It is clear that ERα and ERβ are extremely important components of a complex signal transduction pathway that specifically regulates the growth and development of target tissues and tumors. At the molecular level, ERs act as transcription factors to target a variety of genes using the classical ERE pathway or tethering mechanisms utilizing AP1 or SP1. Usually, transcriptional activity is in response to endogenous ligands such as steroidal estrogens or other ligands such as antiestrogens or
Sandra Timm Pearce is a postdoctoral fellow in the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. After receiving a PhD in biology from the University of Virginia in 2001, she joined the laboratory of Dr. V. Craig Jordan. Dr. Pearce is supported by the Program in Signal Transduction and Cancer (Grant T32-CA70085) and the Avon Foundation. Her research interests include the molecular mechanisms underlying tamoxifen action at the estrogen receptor.
References (194)
On the treatment of inoperable cases of the carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases
The Lancet
(1896)- et al.
Estrogen receptor variants and mutations
J Steroid Biochem Mol Biol
(1997) - et al.
Identification of twenty alternatively spliced estrogen receptor alpha mRNAs in breast cancer cell lines and tumors using splice targeted primer approach
J Steroid Biochem Mol Biol
(2000) - et al.
ER beta: identification and characterization of a novel human estrogen receptor
FEBS Lett
(1996) - et al.
The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro
Biochem Biophys Res Commun
(1998) - et al.
Estrogen receptor beta. Potential functional significance of a variety of mRNA isoforms
FEBS Lett
(2002) - et al.
Estrogen receptor beta in the prostate
Mol. Cell Endocrinol.
(2002) - et al.
Functional domains of the human estrogen receptor
Cell
(1987) - et al.
The human estrogen receptor has two independent nonacidic transcriptional activation functions
Cell
(1989) Estrogen receptor interaction with co-activators and co-repressors
Steroids
(2000)
A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity
J. Biol. Chem.
Agonistic effect of tamoxifen is dependent on cell type, ERE-promoter context, and estrogen receptor subtype: functional difference between estrogen receptors alpha and beta
Biochem. Biophys. Res. Commun.
Phyto-oestrogens and cancer
Lancet Oncol.
A structural biologist’s view of the oestrogen receptor
J. Steroid Biochem. Mol. Biol.
The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen
Cell
Structural insights into the mode of action of a pure antiestrogen
Structure (Camb)
Membrane association of estrogen receptor alpha mediates estrogen effect on MAPK activation
Biochem. Biophys. Res. Commun.
Cellular functions of plasma membrane estrogen receptors
Steroids
The role of mitogen-activated protein (MAP) kinase in breast cancer
J. Steroid. Biochem. Mol. Biol.
Estrogen receptor phosphorylation
Steroids
Estrogen receptor phosphorylation. Hormonal dependence and consequence on specific DNA binding
J. Biol. Chem.
Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity
J. Biol. Chem.
Estradiol-induced phosphorylation of serine 118 in the estrogen receptor is independent of p42/p44 mitogen-activated protein kinase
J. Biol. Chem.
Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance
J. Biol. Chem.
Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin A-CDK2 complex
J. Biol. Chem.
Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1
Mol. Cell
Estrogen receptor pathways to AP-1
J. Steroid Biochem. Mol. Biol.
Unique protein determinants of the subtype-selective ligand responses of the estrogen receptors (ERalpha and ERbeta ) at AP-1 sites
J. Biol. Chem.
Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions
Vitam. Horm.
Ligand-, cell-, and estrogen receptor subtype (alpha/beta)-dependent activation at GC-rich (Sp1) promoter elements
J. Biol. Chem.
Estrogen receptors alpha and beta form heterodimers on DNA
J. Biol. Chem.
Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 1. Receptor interactions
J Med Chem
Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents
J Med Chem
On oophorectomy in cancer of the breast
Br Med J
Basic guides to the mechanism of estrogen action
Recent Prog Hormone Res
Estrogen receptors and breast cancer response to adrenalectomy
Natl Cancer Inst Monogr
Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer
Cancer Res
Selective estrogen receptor modulation and reduction in risk of breast cancer, osteoporosis, and coronary heart disease
J Natl Cancer Inst
Double-blind randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial
J Clin Oncol
Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment
J Clin Oncol
Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability study
J Clin Oncol
Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group
J Clin Oncol
Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group
J Clin Oncol
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial
JAMA
Cloning of the human estrogen receptor cDNA
Proc Natl Acad Sci USA
Sequence and expression of human estrogen receptor complementary DNA
Science
Human oestrogen receptor cDNA: sequence
Nature
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Sandra Timm Pearce is a postdoctoral fellow in the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. After receiving a PhD in biology from the University of Virginia in 2001, she joined the laboratory of Dr. V. Craig Jordan. Dr. Pearce is supported by the Program in Signal Transduction and Cancer (Grant T32-CA70085) and the Avon Foundation. Her research interests include the molecular mechanisms underlying tamoxifen action at the estrogen receptor.
V. Craig Jordan, Diana, Princess of Wales Professor of Cancer Research, director of the Lynn Sage Breast Cancer Research Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, serves as the principal investigator for a National Cancer Institute Special Program of Research Excellence (SPORE) in breast cancer (P50 CA89018-02). His research has been recognized with the receipt of the American Cancer Society’s Medal of Honor, and the Dorothy P. Landon AACR Prize in Translational Research with Elwood V. Jensen. Dr. Jordan was appointed Officer of the Most Excellent Order of the British Empire by Her Majesty the Queen for services to International Breast Cancer Research in 2002. In 2003, Dr. Jordan received the Charles F. Kettering Prize and gold medal from the General Motors Cancer Research Foundation for advances in breast cancer treatment with tamoxifen and the development of SERMs. Dr. Jordan received his PhD, DSc and a Doctor of Medicine degree honoris causa from Leeds University in the UK.