Most evidence supports the view that ERα is responsible for estrogen (ovarian estradiol, E2)-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 E2-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 E2 or ovariectomized WT mice with E2, 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 E2-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 E2, 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 E2, neither ERα nor progesterone receptor was detectable in BrdUrd-labeled nuclei but by 48 h after E2, 29% of the BrdUrd-labeled cells expressed ERα, and 21-38% expressed progesterone receptor. During 3 weeks of continuous E2 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 E2, 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 E2. By down-regulating ERβ, tamoxifen may prolong refractoriness to E2 in mammary epithelium.
|Original language||English (US)|
|Number of pages||8|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Mar 16 2004|
- Progesterone receptor
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