The Cellular Targets Estrogen in Mammary Ductal Development

Abstract

Abstract : It is known that the actions of estrogen in mammary development are mediated primarily by the estrogen receptor alpha (ER alpha). It is not known whether ER alpha in epithelium (the tissue in which breast cancer develops) contribute to mammary cell proliferation and ductal development, or whether ER% target genes with classical estrogen response elements (EREs) or with alternative response elements, especially AP-i and CRE elements, mediate proliferation. We have been successful in developing transgenic mice with expression of wild type and AP-1/CRE superactive human ER alpha (K206A) in mammary gland and reproductive track (vaginal-cervical) epithelium. We use d the keratin 14 gene promoter to drive expression in mammary basal epithelial cells and cervical- vaginal epithelium, and the MMTV promoter to drive expression throughout the mammary epithelium. In the K14 transgenics, expression in the genital tract was efficient and caused hypoproliferation, cyclin D1 over-expression and organ enlargement. Expression of human ERs in the mammary basal cells was less strong, but excessive proliferation and lobular development occurred after estrogen treatment in these animals. We have applied for funding from NIH to finish the study of the mammary gland in these animals and in the MMTV transgenics, which appear to have good expression of the transgene in mammary glands. We tentatively conclude that human ER alpha can function to mediate proliferation in the epithelial cells of the reproductive track and mammary gland, and that the target genes with AP-1/CRE elements are important in this process. If further studies confirm these observations it will suggest that the ER alpha pathway to AP-1/CRE target genes is a key target for interventions to prevent breast cancer.