Differential Roles of ER alpha and ER beta in Normal and Neoplastic Development in the Mouse Mammary Gland

作者：Mehta Rajendra G^*; Hawthorne Michael; Mehta Rajeshwari R; Torres Karen E O; Peng Xinjian; McCormick David L; Kopelovich Levy

来源：PLos One, 2014, 9(11): e113175.

DOI：10.1371/journal.pone.0113175

The present experiments were performed to determine the roles of estrogen receptors alpha and beta (ER alpha and ER beta) in normal and neoplastic development in the mouse mammary gland. In wild-type mice, in vivo administration of estradiol (E) + progesterone (P) stimulated mammary ductal growth and alveolar differentiation. Mammary glands from mice in which the ER beta gene has been deleted (beta ERKO mice) demonstrated normal ductal growth and differentiation in response to E + P. By contrast, mammary glands from mice in which the ERa gene has been deleted (alpha ERKO mice) demonstrated only rudimentary ductal structures that did not differentiate in response to E + P. EGF demonstrates estrogen-like activity in the mammary glands of aERKO mice: treatment of alpha ERKO mice with EGF + P (without E) supported normal mammary gland development, induced expression of progesterone receptor (PR), and increased levels of G-protein-coupled receptor (GPR30) protein. Mammary gland development in beta ERKO mice treated with EGF + P was comparable to that of wild-type mice receiving EGF + P; EGF had no statistically significant effects on the induction of PR or expression of GPR30 in mammary glands harvested from either wild-type mice or beta ERKO mice. In vitro exposure of mammary glands to 7,12-imethylbenz[a] anthracene (DMBA) induced preneoplastic mammary alveolar lesions (MAL) in glands from wild-type mice and beta ERKO mice, but failed to induce MAL in mammary glands from alpha ERKO mice. Microarray analysis of DMBA-treated mammary glands identified 28 functional pathways whose expression was significantly different in alpha ERKO mice versus both beta ERKO and wild-type mice; key functions that were differentially expressed in alpha ERKO mice included cell division, cell proliferation, and apoptosis. The data demonstrate distinct roles for ER alpha and ER beta in normal and neoplastic development in the mouse mammary gland, and suggest that EGF can mimic the ER alpha-mediated effects of E in this organ.

• 出版日期2014-11-18