Estrogens, regulation of p53 and breast cancer risk: a balancing act

The paradoxical effects of ovarian hormones in both the promotion and prevention of breast cancer have been debated for over 30 years. Genetic studies have demonstrated that ovarian hormones act through NF-κB to stimulate proliferation and ductal elongation, whereas the p53 tumor suppressor protein plays a central role in rendering the mammary epithelium resistant to tumorigenesis. Transcriptional profiles now suggest that ovarian hormones stimulate a constellation of genes that interact with NF-κB and p53 to arbitrate the competing demands for proliferation and surveillance. Genes that participate in chromatin remodeling are among the acute transcriptional responses to estrogens and progestins. These genes are proposed to initiate epigenetic programs that influence the balance between proliferation and surveillance, and render the breast epithelium resistant to tumors.