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    Research Grants Awarded

    Regulation of SXR Activation by Rexinoids - Role in Drug Resistance

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    Background: SXR (hPXR) is a nuclear receptor whose transcriptional activity is induced by a variety of drugs, including paclitaxel (Taxol) and Cisplatin. SXR target genes include MDR1 (Pgp), MRP2 and CYP3A4 . Thus, SXR may play a role in induction of chemotherapy resistance by increasing drug metabolism and efflux from cancer cells. SXR functions as a heterodimer with the related nuclear receptor RXR, and the RXR ligand (rexinoid) bexarotene can inhibit development of drug resistance after prolonged treatment of cancer cells with chemotherapy. We found that rexinoids inhibit activation of SXR by the potent SXR agonist Rifampicin, and by Taxol. Rexinoids suppressed activation of transcription from two different, transiently expressed, SXRE-reporters in colon and breast cancer cells. Further, induction of Pgp protein by Rifampicin and Taxol was suppressed by bexarotene. We have begun to elucidate molecular mechanisms involved in this suppression. Objective/Hypothesis: The objectives of this proposal are to examine the molecular mechanism of antagonism between rexinoids and SXR ligands, and to investigate the role of SXR regulation in the development of multidrug resistance. We propose that rexinoids suppress expression of SXR target genes, and hypothesize that this may be a mechanism whereby bexarotene delays the development of resistance of cancer cells to cytotoxic chemotherapy. Specific Aims: 1) Investigate molecular mechanisms whereby rexinoids regulate SXR activity. 2) Correlate regulation by rexinoids and SXR ligands of SXR target genes with the development of resistance to Taxol Study Design: We will use LS180 and MCF-7 cells as our initial model systems, with results to be confirmed in other SXR-positive breast cancer cells and compared to an SXR-negative cell line. We will determine regulation of receptor levels, and protein/protein and protein/DNA interactions will be assessed using mammalian-2-hybrid analysis, co-IP and ChIP. Regulation of SXR target genes will be studied in Taxol resistant MCF-7 and MDA-MB-231, and matching parental cells, and in immortalized BRCA1 mutant cell lines. To further assess the role of SXR, we will use RNAi to downregulate SXR in MCF-7 cells. Potential Outcomes and Benefits: The identification of rexinoids as inhibitors of drug resistance, and understanding of the underlying mechanisms, may allow design of combination therapies that prolong the efficacy of chemotherapy targeting breast cancer.

    Lay Abstract:
    Multidrug resistance is a major cause of failure of cancer chemotherapy. An important factor leading to drug resistance is the presence on tumor cells of proteins that function as drug pumps, pumping chemotherapeutic agents out of the cell. One such protein is P-glycoprotein (Pgp), which is found on 40-50% of breast cancers. Treatment of tumor cells with chemotherapeutic drugs increases the level of Pgp on the cells, leading to resistance. A strategy to improve the efficacy of chemotherapy is therefore to inhibit Pgp. Recently, it was demonstrated that a novel drug, bexarotene (Targretin), could inhibit the development of multidrug resistance in breast cancer cells exposed to commonly used chemotherapeutic drugs, possibly by blocking the increase in Pgp. We propose in this application that bexarotene and other similar drugs might not only inhibit Pgp, but also lower the levels of proteins responsible for the metabolic breakdown of chemotherapeutic drugs. This may lead to increased levels of the drugs inside the tumor cells, improved killing, and reduced resistance. We intend to study the molecular mechanisms that may be responsible for this effect, with the longer-term goal of suggesting novel combination therapies for breast cancer.