Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer

Abstract

Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.European Journal of Endocrinology 150 243-255

A genome-wide study of the repressive effects of estrogen receptor beta on estrogen receptor alpha signaling in breast cancer cells

“…The effects of estrogens are mediated via two estrogen receptor (ER) isoforms, that is, ER alpha (ERa) and ER beta (ERb) (Hanstein et al, 2004). The second ER isoform, ERb, was discovered some 10 years ago (Kuiper et al, 1996).…”

Epigenetic Information and Estrogen Receptor Alpha Expression in Breast Cancer

“…ER-α was believed for many years to be the only ER. ER-β was identified more recently, and it is still subject to ongoing research as to whether mutations and splice variance of this receptor play any role in breast cancer development and/or prognosis and in response to endocrine therapy [6][7][8]. The role of ER-β in breast cancer remains elusive, but the presence of ER-α at the time of diagnosis is an indication for endocrine therapy.…”

Tamoxifen-regulated adenoviral E1A chimeras for the control of tumor selective oncolytic adenovirus replication in vitro and in vivo

“…The molecular basis for this phenomenon, however, is not quite clear. It may be speculated that the liganddependent transactivation domain present in Mer or the ability of Mer to form protein dimers 27 may be involved in enhancing EM function. As discussed above, regulation levels of E1A-Mer chimeras could be further enhanced by deletion of the NLS in EM, although at the cost of a decrease in the absolute viral replication levels.…”

“…25,26 The function of the HBD of steroid receptors is complex, that is, ligand binding, heat-shock protein association, ligand-dependent transactivation and dimerization. 27 In the absence of ligand, HBD fusion proteins seems to be inactivated by a large complex of heat-shock proteins including hsp90, hsp70 and hsp56, most probably through direct interaction of hsp90 with the HBD. 27,28 Binding of a functional ligand leads to an alteration in the structure of the HBD, which allows release of the chimera from hsp90, refolding to an active form and stabilization by dimerization of the HBD.…”

“…27 In the absence of ligand, HBD fusion proteins seems to be inactivated by a large complex of heat-shock proteins including hsp90, hsp70 and hsp56, most probably through direct interaction of hsp90 with the HBD. 27,28 Binding of a functional ligand leads to an alteration in the structure of the HBD, which allows release of the chimera from hsp90, refolding to an active form and stabilization by dimerization of the HBD. 28,29 Several intracellular proteins have been rendered functionally hormone-dependent by fusing them with steroid receptors, among them are several viral and cellular transcription factors like E1A, 26,30 HIV Rev, 31 c-Myc 32 and v-Myb.…”