SELECTIVE RETINOIDS FOR BREAST CANCER THERAPY

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The diversity of the retinoid response is mediated at multiple levels in their signaling pathways by the three retinoic acid and retinoid X receptor (RAR and RXR) subtypes that is compounded by their variation in cell distribution patterns and their direct and indirect mechanisms for modulating gene transcription. Because of this diversity, the potential is high that more effective, less toxic selective retinoids can be identified for the treatment of breast cancer, which will afflict one woman in 12. Mutations in the p53 tumor suppressor genes and resistance to the growth inhibitory effects of retinoids are associated with increased breast tumor malignancy and metastasis. However, we have identified unique classes of retinoids that when used in combination with other retinoids or interferon or by functioning as RAR/RXR panagonists or inducers of apoptosis inhibit the growth and clonal proliferation of normally retinoid-resistant breast cancer cells, regardless of their p53 status. In this Program Project (Selective Retinoids for Selective Retinoids for Breast Cancer Treatment), we propose a multidiscriplinary effort involving four Research Projects and one Core Component to investigate the molecular mechanisms by which retinoids exert their inhibitory effects on breast cancer cells. The resulting knowledge will subsequently allow us to identify the optimum candidates for treatment of this disease. The retinoid design and synthesis efforts of Project Retinoid Design and Synthesis will provide essential probes for mechanism of action studies and candidates for bioevaluation. Project Molecular Mechanism of Retinoid Action will (1) investigate how RARbeta interacts with the betaRARE or is lost in breast cancer and (2) evaluate the targets for their abilities to induce or repress gene transcription. Project Retinoid-Receptor Interaction will (1) study retinoid-induced conformational changes in the RARs and RXRs as heterodimers alone or bound to retinoid response elements; (2) use an in vitro transcription system to assess modulation of the RARbeta response, and (3) characterize the receptor for the retinoid 6-[3-(1-adamantyl)]-2-naphthalenecarboxylic acid (AHPN), which induces apoptosis independently of the retinoid receptors. Project Apoptosis in Breast Cancer will (1) investigate the mechanism of action of AHPN by tracing AHPN apoptotic activity in breast cancer cell lines and isolating the AHP receptor; (2) evaluate AHPN analogs for their inhibitory activity against breast cancer cell growth; and (3) conduct breast cancer xenograft studies on the optimum retinoids/AHPN analogs. The Bioassay Core will conduct (1) retinoid receptor binding studies, (2) an angiogenesis assay, and (3) pharmacologic/toxicological/metabolic assessment to assist the Projects in selecting targets for bioevaluation or use as mechanistic probes by the Decision Network method.