INDUCTION OF APOPTOSIS IN BREAST CANCER

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The Fontana group has identified a retinoid 6-[3-1-adamantyl)-4- hydroxyphenyl]-2-naphthalene-carboxylic acid (AHPN) that induces G1 arrest and subsequent apoptosis in retinoid-resistant human breast carcinoma cells by a retinoid nuclear receptor-independent pathway. Moreover AHPN induced apoptosis in breast cancer cell lines lacking a functional p53 and resistant to growth inhibition of retinoids. Therefore, identification of analogs of AHPN that lack the toxic side effects of retinoids because of their inability to bind to retinoid receptors would offer new therapeutic agents against invasive breast cancer. Project Apoptosis in Breast Cancer will first conduct an investigation to define the mechanism by which AHPN inhibits growth and apoptosis in breast cancer cells, so that improved analogs of AHPN can be more readily identified, then examine the ability of these analogs to modulate breast cancer growth and apoptosis to identify the optimum analogs for treatment of breast cancer and substantiate the mechanism of AHPN action. Specific Aim IV.1. AHPN functions independently of the retinoid receptors to induce G1 arrest and apoptosis through a unique mechanism. Studies will be conducted to determine if this mechanism is (A) binding to an intracellular receptor (B) enhancing gadd 45 promoter transcription through the activation of a trans element, or ~ stabilizing WAF-1 , message through an AHPN- responsive element in its 3'untranslated region. Specific Aim IV.2. AHPN analogs that display enhanced efficacy will be evaluated for their ability to induce G1 arrest and apoptosis, enhance WAF-1 expression, downregulate bcl-XL expression, and enhance chemotherapy-induced apoptosis. Specific Aim IV.3. The AHPN analogs from the Dawson laboratory that display the greatest efficacy (induce apoptosis at concentrations lower than or comparable to AHPN but lack affinity for the retinoid receptors and so will have reduced systemic toxicity) will be assessed for their ability to modulate apoptosis in organ culture of human breast carcinomas. Promising retinoids identified in the Zhang laboratory will be evaluated alone or in combination with chemotherapeutic agents or interferon. Specific Aim IV.4. The optimum three AHPN analogs, retinoids, or retinoid combinations will be assessed for their ability to induce apoptosis and inhibit the growth of human breast carcinoma xenografts in SCID mice.