Estrogen receptor beta binds Sp1 and recruits a corepressor complex to the estrogen receptor alpha gene promoter

Abstract

Human estrogen receptors (ERs) alpha and beta are crucially involved in the regulation of mammary growth and development. Normal breast tissues display a prevalently expression of ER beta than ER alpha, which drastically increases during breast tumorogenesis. So, it is reasonable to assume how a dysregulation of the two estrogen receptor subtypes may induce breast cancer development. However, the molecular mechanism underlying the opposite role played by the two estrogen receptors on tumor cell growth remains to be elucidated. In the present study, we have demonstrated that ER beta overexpression in breast cancer cells decreases cell proliferation and down-regulates ER alpha mRNA and protein content along with a concomitant repression of estrogen-regulated genes. Transient transfection experiments, using a vector containing the human ER alpha promoter region, showed that elevated levels of the ER beta down-regulated basal ER alpha promoter activity. Furthermore, side-directed mutagenesis and deletion analysis have revealed that the proximal GC-rich motifs at −223 and −214 is crucial for the ER beta-induced ER alpha down-regulation in breast cancer cells. This occurred through ER beta-Sp1 protein-protein interaction within the ER alpha promoter region and the recruitment of a corepressor complex containing NCoR/SMRT (nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid hormone receptor), accompanied by hypoacetylation of histone H4 and displacement of RNA polymerase II. Silencing of NCoR gene expression by RNA interference reversed the down-regulatory effect of ER beta on ER alpha gene expression and cell proliferation. Our results provide evidence for a novel mechanism by which overexpression of ER beta through NCoR is able to down regulate ER alpha gene expression, thus inhibiting ER alpha’s driving role on breast cancer cell growth.

Interaction of 14-3-3 proteins with the Estrogen Receptor Alpha F domain provides a drug target interface

“…At the cellular level, the (FC stabilized) interaction between ERα and 14-3-3s negatively affects receptor/DNA interactions, the transactivation activity and ERα-dependent cell growth. Furthermore, this interaction can be targeted by small molecules, like FC, and FC is receptor specific as it only targets ERα without affecting ERβ, which is a positive feature in view of the antiproliferative role described for ERβ (41,42).…”

MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer

“…Recent studies demonstrate that both the ERs can bind to the same ERE and thus share a large number of common target genes, although both ERs also have their distinct downstream targets to regulate unique functions (41,42). This is particularly interesting due to the fact that both the ERs are considered to display opposite functions, with ER-β affecting the ER-α-mediated transcription and eventually cell proliferation (43)(44)(45)(46). However, the cellular effects of estrogen are largely dependent on relative levels of the two ERs displaying complexities associated with differential functions when ER-β is expressed alone versus when it is co-expressed with ER-α.…”

Differential regulation of estrogen receptors α and β by 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol}, a novel resveratrol analog

“…It is well known that expression of ERα is increased and that of ERβ is decreased in early breast cancers [20, 21]. Loss of ERβ in cancer compared to normal tissue has led to the hypothesis that ERβ may function as a tumor suppressor [17, 26]. It is also postulated that ERα and ERβ have opposite biological actions, demonstrating a yin-yang relationship [18].…”

“…Estrogen receptor α has different biological effects than ERβ, and both receptors show different intracellular and tissue distribution patterns [15]. Both, ERα and ERβ are crucial in regulating mammary growth and development [16, 17]. Under normal physiological conditions, ERα mediates the proliferative actions of E2 which can be opposed by ERβ and together, these receptors maintain a subtle balance of estrogen signaling in cells [18].…”

“…Induction of ERβ expression in breast cancer cells has been reported to inhibit estrogen-stimulated proliferation, tumor angiogenesis, and growth in xenograft studies [25]. It has also been suggested that ERβ may function as a tumor suppressor by antagonizing the proliferative effects of ERα [17, 26]. The ratio of ERα:ERβ is now being considered as a better prognostic marker in the diagnosis and therapy of breast cancers [21, 27].…”