Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation.

Abstract

We recently reported that estrogen receptor alpha (ERalpha), even in absence of estrogen (E2), plays a critical role in lactotroph homeostasis. The anti-estrogen ICI 182780 (ICI), but not tamoxifen or raloxifene, rapidly promoted the degradation of ERalpha, and inhibited cell proliferation. However, all three ER antagonists suppressed PRL release, suggesting that receptor occupation is sufficient to inhibit prl gene expression whereas receptor degradation is required to suppress lactotroph proliferation. In this study our objective was to determine whether ERalpha degradation versus occupation, differentially modulates the biological outcome of anti-estrogens.Using the rat lactotroph cell line, GH3 cells, we report that ICI induced proteosome mediated degradation of ERalpha. In contrast, an ERalpha specific antagonist, MPP, that does not promote degradation of ERalpha, did not inhibit cell proliferation. Further, ICI, but not MPP, abolished anchorage independent growth of GH3 cells. Yet, both ICI and MPP were equally effective in suppressing prl expression and release, as well as ERE-mediated transcriptional activity.Taken together, our results demonstrate that in lactotrophs, ERalpha degradation results in decreased cell proliferation, whereas ERalpha occupation by an antagonist that does not promote degradation of ERalpha is sufficient to inhibit prl expression.