BRCA Genes in Breast Cancer Chemoprevention

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DESCRIPTION (provided by applicant): Background. Clinical-epidemiological and animal model studies suggest that indole-3-carbinol [I3C, a phytochemical from cruciferous vegetables] has chemopreventive activity for hormone-dependent tumor types, including breast, cervical, and endometrial cancers. Its anti-tumor activity is probably due to both hormone-dependent and hormone independent actions. Mutations of the breast cancer susceptibility genes BRCA1 and BRCA2 each confer a significantly increased risk of several hormonally-responsive cancer types (e.g., breast and prostate cancers). Preliminary studies. Our published and preliminary studies suggest that some of the hormone-dependent and hormone-independent actions of DC in human breast, cervical cancer, and prostate cell lines are mediated through the up-regulation of BRCA1 and BRCA2 expression. Gene expression profiling using DNA microarrays suggest an overlap between the gene expression patterns induced by DM (the major active metabolite of ISC) vs BRCA1. Hypothesis. We postulate that chemoprevention by I3C is due, in part, to BRCA1 (and probably BRCA2) mediated activities: e.g., inhibition of E2-stimulated cell growth and up-regulation of growth arrest and DNA damage-responsive genes (GADDs) and GSTs. I3C may also induce these and other tumor suppressor pathways independently of BRCA1; and BRCA1/2 may function synergistically with these other I3C pathways to suppress tumorigenesis. Objectives. To test these hypotheses, we will carry out three specific aims. In SA1, we will investigate the mechanism by which I3C induces BRCA1 and BRCA2; and we will assess the contribution of the endogenous BRCA genes to the estrogen-dependent and estrogen-independent molecular and cellular actions of I3C in human mammary epithelial cells, using small interfering RNAs to each BRCA gene that we have already developed. In SA2, we will assess the roles of the BRCA genes in the spectrum of DBVI-induced transcriptional alterations in mammary epithelial cells. And in SA3, we will validate some of these in vitro observations using two in vivo experimental models for prevention of mammary cancer by dietary supplementation with I3C. One model will feature a mammary-targeted mutation of Brcal. Significance. These studies will establish that the BRCA genes are molecular targets for indole-3-carbinol that contribute to its ability to prevent breast cancer. A successful outcome of these studies would suggest the use of I3C in chemoprevention of sporadic and hereditary breast cancers. The latter may be particularly useful, since recent studies suggest that Tamoxifen may not protect women with BRCA1 mutations from developing breast cancer.