BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

Abstract

Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

The role of early life genistein exposures in modifying breast cancer risk

“…It is not known whether all these changes (or none of them) lead to a reduction in mammary cancer risk. The complexity between genistein/soy, the genes it activates/inhibits, and breast cancer risk are also illustrated by the fact that genistein activates ER-a, which in turn interacts with BRCA1 (Fan et al, 2006) and PTEN (Lian et al, 2006). The causality between the changes in gene expression induced by genistein/soy intake and altered breast cancer risk can be addressed at least partly by using genetically modified mouse models such as Brca1 or Pten knockout mice.…”

“…In vitro studies have shown that physiological doses of genistein (0.5 -1.0 mM) upregulate BRCA1 in ER þ human breast cancer cells and in prostate cancer cells (Fan et al, 2006). In addition, genistein upregulates the expression of both Brca1 and Brca2 mRNA in adult ovariectomised rats (Vissac-Sabatier et al, 2003).…”

Breast cancer: Small molecules targeting apoptosis, a prospective approach to safe scientific success

“…The pro-survival (antiapoptotic) members Bcl-2, Mcl-1, Bcl-xl, Bcl-w contain a BH1, BH2, and BH3, but with the exception of Mcl-1, they also contain a BH4 domain. The last group, which are the proapoptotic members including Bid, Bad, Bik, Bim, Puma, and Noxa only have a BH3 domain [37] (Figure 1).…”

The effect of indole-3-carbinol on PIN1 and PIN2 in Arabidopsis roots

“…2,3 In humans, a rich cruciferous vegetables diet has been associated with reduced chances of cancer, and I3C as a therapeutic treatment has potential for both prevention and treatment of a wide verity of cancers, such as leukemia, breast cancer and prostate cancer among others. [4][5][6][7][8] In Arabidopsis thaliana I3C is synthesized upon tissue rapture and deters herbivores. The glucosinolates and the myrosinase are normally stored in separate compartments in the plant cells.…”