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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Rosen, Eliot M; Pishvaian, Michael J (2014) Targeting the BRCA1/2 tumor suppressors. Curr Drug Targets 15:17-31
Fan, Saijun; Meng, Qinghui; Xu, Jiaying et al. (2013) DIM (3,3'-diindolylmethane) confers protection against ionizing radiation by a unique mechanism. Proc Natl Acad Sci U S A 110:18650-5
Karve, Tejaswita M; Rosen, Eliot M (2012) B-cell translocation gene 2 (BTG2) stimulates cellular antioxidant defenses through the antioxidant transcription factor NFE2L2 in human mammary epithelial cells. J Biol Chem 287:31503-14
Saha, Tapas; Rih, Jeong Keun; Roy, Rabindra et al. (2010) Transcriptional regulation of the base excision repair pathway by BRCA1. J Biol Chem 285:19092-105
Fan, Saijun; Meng, Qinghui; Saha, Tapas et al. (2009) Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 69:6083-91
Ballal, Rahul D; Saha, Tapas; Fan, Saijun et al. (2009) BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage. J Biol Chem 284:36083-98
Hong, Young Bin; Kang, Hyo Jin; Kim, Hee Jeong et al. (2009) Inhibition of cell proliferation by a resveratrol analog in human pancreatic and breast cancer cells. Exp Mol Med 41:151-60
Saha, Tapas; Rih, Jeong Keun; Rosen, Eliot M (2009) BRCA1 down-regulates cellular levels of reactive oxygen species. FEBS Lett 583:1535-43
Rosen, Eliot M; Fan, Saijun; Ma, Yongxian (2006) BRCA1 regulation of transcription. Cancer Lett 236:175-85
Fan, S; Meng, Q; Auborn, K et al. (2006) BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 94:407-26