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Estrogen Receptor- Mediates the Epidermal Growth Factor-Stimulated Prolactin Expression and Release in Lactotrophs

Department of Cancer and Cell Biology (N.B.-J., J.A.D., C.L., S.K.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Departments of Endocrinology, Metabolism and Clinical Nutrition (S.C., S.K.), and Pharmacology (S.K.), Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Address all correspondence and requests for reprints to: Sanjay Kansra, Departments of Endocrinology, Metabolism and Clinical Nutrition, and Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. E-mail: skansra{at}mcw.edu.

Epidermal growth factor (EGF) is a potent regulator of cell function in many cell types. EGF-receptor (EGFR/ErbB1)-activated Erk1/2 has been reported to activate estrogen receptor (ER) in an estrogen (E2)-independent manner. In the pituitary lactotrophs, both EGF and E2 stimulate prolactin (PRL) release, but the nature of interactions between ErbB and ER signaling is unknown. Our objectives were to 1) characterize EGF-induced PRL release, 2) determine whether this effect requires ER, and 3) determine the molecular basis for cross talk between ErbB and ER signaling pathways. Using GH3 cells, a rat lactotroph cell line, we report that EGF stimulates PRL gene expression and release in a dose- and time-dependent manner. EGF caused a rapid and robust activation of Erk1/2 via ErbB1 and induced phosphorylation of S118 on ER in an Erk1/2-dependent manner. The global antiestrogen ICI 182780 and the ER-specific antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylet hoxy)phenol]-1H-pyrazole dihydrochloride (MPP), but not the ERβ-specific antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), blocked the EGF-induced PRL release, indicating an ER requirement. This was further supported by using ER knockdown by small interfering RNA. Because the antiestrogens did not block EGF-induced Mek-1 or Erk1/2 phosphorylation, ER is placed downstream from the ErbB1-activated Erk1/2. These results provide the first evidence that ErbB1-induced PRL release is ER dependent.

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