Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland

Abstract

Most evidence supports the view that ERα is responsible for estrogen (ovarian estradiol, E 2 )-induced proliferation in the epithelial cells of the mammary gland, but despite this, proliferating epithelial cells do not express ERα. We have examined this apparent paradox by studying the role of ERα and ERβ in E 2 -induced proliferation in mammary glands (measured by BrdUrd incorporation into DNA) in mice with intact ERβ (WT mice) and those in which the ERβ gene has been inactivated (ERβ -/- mice). On treatment of ERβ -/- mice with E 2 or ovariectomized WT mice with E 2 , tamoxifen, or a specific ERβ agonist (BAG), the number of BrdUrd-labeled cells in mammary glands increased from 3.4% in controls to 28-38% in the treated mice. This indicates that both ERα and ERβ can mediate E 2 -induced proliferation independently of each other. With specific antibodies, ERβ was found in both epithelial and stromal cells, whereas ERα was strictly epithelial. Within 4 h of a single dose of E 2 , ERα was lost from the nuclei of epithelial cells. In WT mice, ERα reappeared by 24 h, but in ERβ -/- mice, return to the nucleus was delayed by 24 h. At 4 h after E 2 , neither ERα nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E 2 , 29% of the BrdUrd-labeled cells expressed ERα, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E 2 treatment, ERβ remained in the nucleus, but there was no detectable ERα. With tamoxifen treatment, ERα remained in the nucleus, but ERβ was lost. From these results, we conclude that ERα receives the proliferation signal from E 2 , initiates DNA synthesis, and is then lost from cells. The subsequent steps in proliferation can proceed in the absence of either ERα or ERβ. ERβ facilitates the return of ERα to the nucleus and restores responsiveness to E 2 . By down-regulating ERβ, tamoxifen may prolong refractoriness to E 2 in mammary epithelium.

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…The diminished ER expression must be due either to downregulation of ER expression in ER þ tumor cells or to selection against the ER þ subset of tumor cells. With regard to the first possibility, we found that tamoxifen did not downregulate ER in the adjacent normal ducts (data not shown), suggesting that the loss of ER in treated tumors is not caused by downregulation of ER expression by tamoxifen, consistent with reports in cultured breast cancer cell lines (Giamarchi et al, 2002;Cheng et al, 2004). To confirm this in the tumor cells themselves, we examined ER expression in three sets of transplanted tumors that had been treated with tamoxifen for only 5 days, when the ER þ cell population would not yet be selected out.…”

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

“…In wild-type mice, chronic estrogenic stimulation, but not chronic tamoxifen treatment, results in downregulation of nuclearlocalized ERa. In contrast, chronic tamoxifen stimulation results in downregulation of nuclear-localized ERb but not ERa (Saji et al, 2000;Cheng et al, 2004). We hypothesized that if the relative agonist activity of tamoxifen was increased by loss of full-length Brca1, there would be loss of nuclear-localized ERa with retention of nuclear-localized ERb in the hyperplasias of the tamoxifen-treated Brca1 Co/Co MMTV-Cre/p53 þ /À mice.…”

“…In normal mice, tamoxifen treatment results in regression of mammary ductal structures (Kotoula et al, 1993) and, tamoxifen, unlike chronic estrogen treatment, does not downregulate levels of nuclear-localized ERa (Cheng et al, 2004). It does, however, downregulate levels of nuclear-localized ERb (Cheng et al, 2004). Tamoxifen can prevent progression of ERa-negative cancers in certain mouse models (Osborne et al, 1990;Yoshidome et al, 2000;Yang et al, 2003).…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Analysis of estrogen receptor proteins in rat mammary gland has shown that both types of ERs are expressed and the results from ERα-KO and ERβ-KO mice reveal that ERα is necessary for mammary gland development. ERβ co-expression with ERα has been suggested to repress ERα's function and may contribute to the insensitivity of the mammary gland to estrogen during lactation [31,32]. Deletion of ERα, which mediates the E2 action in mice, results in a rudimentary ductal system that fails to branch out [33].…”