HORMONE-INDUCED REFRACTORINESS TO MAMMARY, CARCINOGENESIS IN WISTAR-FURTH RATS

One of the most consistent results in the epidemiology of human breast cancer is the inverse relationship of risk and early full-term parity , The goal of this study was to investigate the molecular mechanisms t hrough which early full-term pregnancy protects the breast from cancer development. We used Wistar-Furth (WF) rats as our experimental syste m and mimicked pregnancy using estrogen and progesterone (E/P), Sexual ly mature female rats were treated with steroid hormones for 21 days a nd after 28 days of gland involution, the rats were administered MNU, Rats that received a high dose of 20 mu g E and 20 mg P exhibited an 8 2% reduction in the incidence of mammary adenocarcinomas as compared t o the rats receiving only blank pellets, Decreasing doses of E/P were partially protective suggesting that complete differentiation of the g land was not required for refractoriness. We measured the RNA expressi on levels of several target genes involved in the regulation of mammar y cell proliferation and/or differentiation including estrogen recepto r (ER) and progesterone receptor (PR), cyclins DI and D2, the cell cyc le inhibitors p16,p21 and p27, and the tumor suppressor p53, At the ti me of MNU treatment we found no significant differences in the express ion of these genes, with the possible exception of p21, indicating tha t hormone treatment did not result in constitutive changes in expressi on levels, The numbers of apoptotic cells were low and comparable in t he hormone exposed and age-matched virgin gland (AMV) at the time of c arcinogen challenge and remained low for 8 days after MNU treatment, T he number of BrdU-labeled cells at the time of carcinogen challenge we re also low in both the AMV (1.8%) and hormone exposed (0.8%) animals, In contrast, cell proliferation in the AMV (5.7%) was significantly d ifferent from both the parous involuted (1.2%) and the E/P-treated inv oluted (1.5%) animals 8 days after MNU treatment, We interpret these d ata to indicate that hormone treatment results in mammary epithelial c ells that have persistent alterations in intracellular pathways govern ing proliferation responses to carcinogens.