selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation选择性雌激素受体装置和选择性雌激素受体调节剂不同调节lactotroph扩散.pdfVIP

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation 1,2,3 2 2 1 Sanjay Kansra *, Shenglin Chen , Madhavi Latha Yadav Bangaru , Leighton Sneade , Joseph A. Dunckley1, Nira Ben-Jonathan1 1 Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America, 2 Department of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America, 3 Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America Abstract Background: We recently reported that estrogen receptor a (ERa), 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 ERa, 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 ERa degradation versus occupation, differentially modulates the biological outcome of anti-estrogens. Principal Findings: Using the rat lactotroph cell line, GH3 cells, we report that ICI induced proteosome mediated degradation of ERa. In contrast, an ERa specific antagonist, MPP, that does not promote degradation of ERa, did not inhibit cell proliferation. Further, ICI, but not MPP, abolished anchorage independent growth of