Regulation of the p53 Tumor Suppressor Gene and Susceptibility to Breast Cancer.
Reproductive factors and family history of breast cancer are among the most consistent predictors of an individual’s risk of developing breast cancer. These observations emphasize the important contributions of both genetic background and hormonal exposures in determining the risk of breast cancer. Through the use of contemporary techniques in molecular and cellular biology with animal models, we are defining the developmental biology of the breast epithelium itself, while providing both a genetic and cellular basis for susceptibility to breast cancer.
The p53 tumor suppressor protein is a major focus of the laboratory because its pivotal role in cancer. In addition to its role in genome surveillance, we found that loss of p53 allows expansion of the mammary stem cell population and this can be reversed by inhibition of Notch. Surprisingly, the fundamental actions of p53 on genome surveillance are enhanced by hormonal stimuli during pregnancy and contribute to the reduction in mammary tumors afforded by a full-term pregnancy. Administration of exogenous estrogen was sufficient to mimic the effect of pregnancy. Although estrogen stimulates proliferation, it also potentiates the p53-mediated apoptosis. These duplicitous actions of estrogens appear to be regulated through distinct estrogen receptors. Therefore, selective activation of the genome surveillance actions can be harnessed for the prevention of breast cancer and adjuvant therapies for those tumors with functional p53.
The frequent mutation of p53 in breast cancer reflects its critical role. However, in mice bearing mutations in p53, the incidence of mammary tumors differs dramatically among strains. Naturally-occurring variants in homology-directed DNA repair have revealed a profound role for this pathway in determining risk of mammary tumors. We are also determining gene expression profiles premalignant breast lesions. These studies provide the basis for diagnostic tests defining which patients are at high risk and should consider treatments while also providing insights into the molecular basis for premalignancy in the human breast.
Terry MB, Michels KB, Brody JG, Byrne C, Chen S, Jerry DJ, Malecki KMC, Martin MB, Miller RL, Neuhausen SL, Silk K, Trentham-Dietz A; Breast Cancer and the Environment Research Program (BCERP). Breast Cancer Res. 2019 Aug 20;21(1):96. doi: 10.1186/s13058-019-1168-2. Review. Environmental exposures during windows of susceptibility for breast cancer: a framework for prevention research. PMID: 31429809. Free PMC Article. Similar articles
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