Role of the Steroid and Xenobiotic Receptor (SXR) in Drug Resistant Breast Cancer

摘要

The rationale for the work in this proposal was based on the observations that: 1) SXR, a recently-characterized member of the nuclear steroid receptor family, is expressed to varying degrees in normal and neoplastic breast tissues; 2) the anticancer agent Taxol acts as a ligand for SXR and can activate the transcriptional activity of SXR in the context of an SXR-reporter gene construct; 3) Taxol activation of SXR in primary human cells results in increased expression of endogenous human cytochrome P45O 3A4 (CYP3A4) and multidrug resistance-1 (MDR 1) genes, leading to increased rates of Taxol metabolic inactivation and efflux; and 4) Taxotere, a structurally- and mechanistically-related taxane, is a much less potent activator of SXR in human tissues and taxotere does not induce its own metabolism and extracellular transport. We hypothesized that breast cancer cells that overexpress SXR would be resistant to treatment with Taxol through auto- induction of CYP3A4 and MDR1, while sensitivity to taxotere would be unaffected. We further hypothesized that SXR- mediated induction of CYP3A4 and MDR1 might contribute to clinical multidrug resistance in breast cancer. The objectives of this proposal were to 1) determine if overexpression of SXR in breast cancer cells leads to elevated expression of CYP3A4, MDR1, and other drug resistance-associated genes; and 2) determine if SXR, CYP3A4, MDRl, and other drug resistance-associated genes are coordinately expressed in primary human breast tissues.