Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Abstract

39 AIB1 = amplified in breast cancer; AF-1 = activation function-1; AF-2 = activation function-2; cAMP = cyclic AMP; CBP = CREB-binding protein; DES = diethylstilbestrol; E2 = 17β-estradiol; ER = estrogen receptor; ERE = estrogen response element; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; FDA = Food and Drug Administration; HAT = histone acetyltransferase; IGF1 = insulin-like growth factor-1; LBD = ligand-binding domain; MAPK = mitogen-activated protein kinase; NR = nuclear receptor; PKA = protein kinase A; SERM = selective estrogen receptor modulator.Available online http://breast-cancer-research.com/content/6/1/39 IntroductionEstrogen receptors (ERs) are members of the nuclear receptor (NR) superfamily that mediate the pleiotropic effects of the steroid hormone estrogen in a diverse range of developmental and physiological processes [1]. Although estrogens are important physiological regulators in the reproductive system, in bone metabolism, and in the maintenance of the cardiovascular and central nervous systems, they have also been associated pathologically with an increased risk for breast and endometrial cancer [2][3][4][5]. Consequently, ERs have been found to be essential in the initiation and development of most of these cancers. Current endocrine therapies for ER-positive breast cancers are primarily designed to target either estrogen or ER levels and/or activity. Use of a partial antiestrogen, tamoxifen, in the management of early-stage breast cancer has clearly demonstrated an increase in both disease-free and overall survival. In addition, recent studies demonstrate that tamoxifen can be used as a chemopreventive agent for hormone-dependent breast cancer. The major concerns of long-term therapy with tamoxifen are its uterotropic effects, which result in an increased risk for endometrial cancer, and the acquired clinical resistance to tamoxifen. This has led to the active pursuit of better selective ER modulators (SERMs) that display the optimal agonistic or antagonistic activities in various estrogen target tissues.In this article we review the emerging studies of ER action that reveal the roles of a wide spectrum of receptor coregulators and their interaction with other cellular signaling pathways. An understanding of the molecular factors that modulate the activity of the estrogen-signaling network provides insight into the mechanism by which SERMs exert their tissue-specific effects. The identification of factors that are responsible for such effects is enabling the development of new ways to overcome resistance to endocrine therapy. Review Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy AbstractEstrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These i...

Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

“…Hormone replacement therapy is the use of exogenous estrogen in order to maintain certain normal functions in the body. The use of phytoestrogens as a replacement of estradiol being used in HRT to decrease cancer risk is then developed, thus categorized as chemopreventive agents (Shao & Brown, 2003). Not only phytoestrogens, compounds possessing antioxidant activity are also potential as chemopreventive agents (Seely et al, 2005).…”

Breast Cancer, Estrogen Receptor and Ligands

“…Ligand-binding experiments revealed high affinity and specific binding of E2 to both ER isotypes, and no obvious differences between the two isotypes alone or combined were observed in ERE transcriptional assays in the presence of E2 [46]. ER-mediated transcription is a highly complex process involving a multitude of coregulatory factors and "cross-talk" between distinct signaling pathways [47,48], which could be depicted in a mode including ligand-dependent and ligand-independent ER transcriptional activations (Figs. 6 and 7) [9,47,2].…”

“…ER-mediated transcription is a highly complex process involving a multitude of coregulatory factors and "cross-talk" between distinct signaling pathways [47,48], which could be depicted in a mode including ligand-dependent and ligand-independent ER transcriptional activations (Figs. 6 and 7) [9,47,2].…”

“…These include signaling pathway (ii) regulated by membrane ER (mER), and modulation of ER activity by growth factors (including epidermal growth factor, insulin-like growth factor-1, insulin, and transforming growth factor-b), neurotransmitters such as dopamine, and second messengers such as cAMP and others that affect protein kinase cascades including the MAP kinase signaling pathway (iii), and (iv) (Fig. 7) [2,47,9].…”

“…some tissues, e. g. bone and the cardiovascular system. These biological selectivities in different tissues may be explained, by the nature of the ligands, by both the multitude of transcription factors and cofactors in the modes, i. e., how they take part in the mode of action, and the differences and particularities of various tissues [47,104,18]. For instance, (i) different transcription factors (or subtypes) such as ERa and ERb can regulate different, even opposing biological events with a same ligand; (ii) different cofactors such as co-activators or corepressors possess different recognition features for the ER; (iii) specific EREs or a particular promoter that interacts with the altered ligand-ER complex result in a corresponding response; (iv) different intracellular environments influence or even determine the ligands' biocharacter through different signaling pathways.…”