SXR, A Novel Target for Breast Cancer Therapeutics
Annual summary rept. 1 Apr 2006-31 Mar 2007
CALIFORNIA UNIV IRVINE
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Anti-estrogens such as tamoxifen are important therapeutic agents in the treatment and chemoprevention of breast cancers. Other compounds such as phytoestrogens, fatty acid amides such as anandamide and retinoid X receptor agonists are also effective against breast cancer in cell lines and in animal models. Because these compounds are structurally unrelated, it has not been appreciated that they might act through a common mechanism. All of these compounds share the ability to activate a heterodimer of the steroid and xenobiotic receptor SXR and retinoid X receptor RXR. Our hypothesis is that SXR serves as a common molecular target for some of the anti-proliferative effects of these compounds and that activation of SXR is itself anti-proliferative. To this end, we have found that activation of SXR leads to apoptosis and G1 cell cycle arrest through a p53 dependent pathway in estrogen receptor positive MCF7 breast cancer cells. In this period of study, we have confirmed our initial results in another ER breast cancer cell line ZR-75-1. We have also been able to provide further support for our hypothesis by showing that activation of SXR not only causes increase in p53 mRNA, but also causes stabilization and accumulation of p53 protein in MCF7 cells. So far, we have been able to significantly knock down SXR in MCF-7 cells by using siRNA and we are currently performing the loss of function studies in these cells and optimizing the siRNA transfection conditions in ER- breast cancer cell lines.
- Medicine and Medical Research