A Target for Breast Cancer Prevention and Treatment

Abstract

Abstract : Anti-estrogens such as tamoxifen are important therapeutics for treatment and chemoprevention of breast cancers. Other compounds such as phytoestrogens and fatty acid amides are also effective against breast cancer proliferation. These compounds share the ability to activate the steroid and xenobiotic receptor (SXR). Our hypothesis is that SXR serves as a common molecular target for the anti-proliferative effects of these compounds and activation of SXR is itself anti-proliferative. We have detected SXR protein in breast cancer cell lines, and have shown that either SXR activators or a constitutively active form of SXR are able to slow the proliferation of breast cancer cells. We found that SXR activators share the ability to increase the expression of inducible nitric oxide synthase in MCF-7 cells leading to an increased production of reactive nitrogen species. In SXR activator treated cells, we found that p53 expression as well as the p53 target genes p2l and BAX were increased. Apoptosis occurred in cells treated with SXR activators and is likely the reason for the observed decrease in cell proliferation. Activated/stabilized p53 due to cellular stress from increased reactive nitrogen species provides a mechanism explaining the apoptotic response and decreased proliferation in the presence of SXR activators.