Since this is a new project any synopsis will consist for the most part, of proposed experiments. The relatively high incidence of carcinoma of the breast among women in the United States has prompted the need to understand the biochemical basis for susceptibility of this disease. Ovarian estrogens, which are considered essential for the growth of mammary ducts during puberty, apparently have a critical role as growth promoters in mammary cancer. In one study we are investigating the potential for local growth factor pathways to mediate estrogen-stimulated mouse mammary cell growth. We are specifically investigating the potential role of polypeptides that activate the epidermal growth factor (EGF) receptor, since previous studies have shown that isolated mammary epithelial cells are highly sensitive in vitro to the mitogenic actions of EGF. Efforts to immunolocalize EGF or the EGF precursor in mammary cells of young CD-1 mice have yielded negative results so far and in vivo pellets containing anti-EGF IgG have failed to inhibit elongation of the ducts in young mice. We are also investigating the potential fOr - transforming growth factor ( TGF) to function as an autocrine factor since this polypeptide also has EGF-receptor activity. In other studies, we found that prepro EGF mRNA ( 4.7 kilobases) was elevated in the mouse lactating mammary gland. Since the lactating gland exhibits negligible cell proliferation, we propose that the EGF precursor is processed to elaborate EGF at the cell surface as a constituent of milk. In another study, we are examining the permanent influence that early full-term pregnancy exerts on the capacity of the mouse mammary gland to repair DNA adducts following treatment with 7,12-dimethylbenzanthracene (DMBA), a mammary procarcinogen. It is well known that early full-term pregnancy is a negative risk factor in human breast cancer. We plan to utilize the 32P-postlabeling method to monitor the type and level of adduct formed in vivo in nonparous and parous animals.
