The high incidence of breast cancer among females in the U.S. has prompted the need to understand the epidemiological and biochemical factors that contribute to susceptibility of this disease. Ovarian steroids are considered to have a promotional or permissive role in breast cancer but little is known how these compounds function in stimulating proliferation of normal or neoplastic mammary cells. Estrogens can stimulate formation of several polypeptide growth factors in breast carcinoma cell lines and the normal mammary gland synthesizes transforming growth factor-alpha (TGF- alpha) and epidermal growth factor at different stages of development. These findings suggest that the proliferative actions of estradiol or progesterone may be mediated by local growth factors. We are currently investigating the ovarian, pituitary, and local gland factors that contribute to the cyclical pattern of DNA synthesis in the adult mammary gland. The mouse and human mammary glands are similar in that estrogens alone, which stimulate uterine and vaginal epithelial cell proliferation, are weak mitogens for the adult mammary gland. Cytokinetic studies revealed that pronounced incorporation of bromodeoxyuridine occurs in estrogen-receptor positive lumenal epithelial cells of the gland in the luteal phase of the estrous cycle of the CD-1 mouse. Experimental studies with ovariectomized mice suggest that estradiol plus progesterone are critical for cyclical DNA syntheses of the gland epithelium. We are also investigating the contribution of pituitary factors such as prolactin to cell proliferation in the gland since this hormone is mitogenic to normal mouse mammary epithelial cells in vitro, especially in combination with progesterone. The appearance of EGF in mammary epithelial cells of adult rodents led us to consider this growth factor as a mediator of estrogen-progesterone induced growth but neither of these steroids, alone or in combination, augment prepro EGF-mRNA in the gland. But it is conceivable that other local peptide growth factors that can utilize the EGF receptor or other novel pathways may be regulated by and mediate ovarian steroid induced growth in the gland in adult animals.
