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Characterization of G protein-coupled estrogen receptor (GPER) in breast epithelial proliferation and morphogenesis

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Please use this identifier to cite or link to this item: http://hdl.handle.net/1928/20875

Characterization of G protein-coupled estrogen receptor (GPER) in breast epithelial proliferation and morphogenesis

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Title: Characterization of G protein-coupled estrogen receptor (GPER) in breast epithelial proliferation and morphogenesis
Author: Scaling, Allison
Advisor(s): Hathaway, Helen
Committee Member(s): Prossnitz, Eric
Orlando, Rob
Bisoffi, Marco
Department: University of New Mexico. Biomedical Sciences Graduate Program
Subject: GPER, GPR30, Estrogen, Estrogen Receptor, Breast, Proliferation
LC Subject(s): Estrogen--Receptors.
Estrogen.
Cell proliferation ǂx Molecular aspects.
Cell adhesion--Molecular aspects.
Breast--Physiology.
Degree Level: Doctoral
Abstract: Estrogen (17β-estradiol, E2) plays an important role in regulating an array of functions in both male and female reproductive physiology. In the mammary gland, E2-induced proliferation, ductal outgrowth and subsequent branching morphogenesis is required for proper development of the breast. In males, E2 is required for proper testicular development, spermatogenesis, and sperm maturation in the epididymis, but can also negatively regulate these functions with inappropriate exposure. The effects of E2 in these organs have long been attributed to classical estrogen receptors (ERα and ERβ), due to the observed effects in ER-/- mice; however, GPER is abundantly expressed in male and female reproductive organs, including the breast, testes and epididymis, and there is increasing evidence that GPER contributes to E2-induced functions in these tissues. For this study, we were interested in the contribution of GPER to E2-induced processes in 1) the breast; proliferation and morphogenesis, 2) the testes; regulation of spermatogenesis and morphology, and 3) the epididymis; specifically morphological regulation. Since proliferation and morphogenesis in the mammary gland are under tight E2 control and GPER is able mediated E2-induced proliferation in breast cancer cells, we were interested to see if GPER mediates E2-induced proliferation and morphogenesis in breast epithelial cells (MCF10A cell line) and in human breast tissue. E2 and G-1 stimulation in human breast tissue led to significant increase in proliferation measured by Ki-67 staining, and led to distinct morphological changes including an E2-induced increase in epithelial height in alveolar structures and a G-1-induced increase in luminal area after seven days in culture. E2-and G-1 also stimulated proliferation in MCF10A cells and this is dependent on epidermal growth factor receptor (EGFR) transactivation and mitogen activated protein kinase (MAPK) activation. Other observations in chapter 3, including a G-1-induced reduction in E-cadherin protein expression (breast tissue) and a G-1-induced increase in focal adhesion kinase (FAK) activation (MCF10A cells) suggest that regulation of GPER-mediated morphological changes involves regulation of cell-cell adhesion proteins. To determine the contribution of GPER to E2-induced spermatogenesis and morphology in male reproductive organs, we subcutaneously implanted C57BL/6 male mice with 21-day release E2 and G-1 pellets, and then investigated morphological effects on the testes and epididymis. G-1 had no effect on spermatogenesis or testicular morphology (unlike estrogen which impairs proper testicular morphology and abolishes spermatogenesis); however, G-1 treatment significantly increased the luminal area of epithelial structures in the epididymis. We have demonstrated in this study that while GPER doesn’t mediate the entirety of estrogen’s effect in female and male reproductive physiology, GPER-contributes to E2-induced proliferation in the mammary gland and to the regulation of morphogenesis of epithelial structures in the breast and the epididymis.
Graduation Date: May 2012
URI: http://hdl.handle.net/1928/20875


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