Pregnancy provides significant protection against breast cancer for women that give birth before the age of 20. Early menarche in women has, on the other hand, been associated with increased risk for breast cancer development. As yet, it is not understood how different physiological phenomena affect breast cancer incidence. However. both pregnancy and ovulation are characteristic of elevated concentrations in serum of a variety of hormones, many of which also regulate the development of the mammary gland and have been found to affect mammary carcinogenesis. In this application, we proposed to continue to investigate different physiological conditions that affect mammary carcinogenesis using the rat as an animal model. We have found that parous rats that are refractory to chemically induced mammary tumors have reduced circulating concentration of growth hormone (GH), and prolactin (PRL) concentration in serum was also somewhat reduced levels of estrogen receptors on the mammary gland. We hypothesize that these hormonal and receptor changes play a decisive role in reducing the susceptibility to chemically induced mammary tumorigenesis found in parous rats. We will in the studies proposed here determine which hormones are important for the susceptibility of the mammary gland to chemically induced carcinogenesis, how the different hormones interact with each other to regulate the susceptibility of the mammary gland, and we will also begin to elucidate the effect that these hormones have on the mammary gland to yield cells either refractory or susceptible to carcinogenesis. Toward these ends, we will first carry out experiments where mammary tissue and isolated mammary epithelial cells obtained from susceptible rats will be transplanted to refractory hosts and vice versa to determine whether refractory to carcinogenesis in an appropriate hormonal environment. We will then manipulate the concentration in serum of mammotropic hormones in rats to acquire hormonal profiles that are associated with high and low susceptibility to chemically induced mammary cancer. These animals will then be injected with carcinogen and tumor incidence compared with intact animals. In addition, we will examine how different hormonal profiles yield different mammary cell phenotypes and how the different phenotypes related to differences in the susceptibility to mammary tumorigenesis.
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