The biological role of estrogen receptors α and β in cancer

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Abstract

The temporal and tissue-specific actions of estrogen are mediated by estrogen receptors α and β. The ERs are steroid hormone receptors that modulate the transcription of target genes when bound to ligand. The activity of these transcription factors is regulated by a variety of factors, including ligand binding, phosphorylation, coregulators, and the effector pathway (ERE, AP1, SP1). The end result of target gene transcription is to modulate physiological processes, such as reproductive organ development and function, bone density, and unfortunately contribute to the growth and development of breast and endometrial cancer. The complex biological effects mediated by ERα and ERβ involve communication between many proteins and signaling pathways. An ultimate goal of current research is to enhance the value of the separate estrogen receptors as targets for therapeutic intervention.

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.

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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.

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