3147 Background: Most metastatic breast cancers initially respond to hormonal treatment but all become resistant to these treatments over time. The genetic events that occur during acquired resistance are unknown. To examine the gene expression changes during acquired hormonal resistance, we used a model that mimics ER positive breast cancers in the post-menopausal setting with the tumors responsive to both Tamoxifen (TAM) and aromatase inhibitors. Tumors were analyzed with high density cDNA microarrays to identify genes associated with TAM resistance. Methods: Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumor xenografts in female ovariectomized athymic nude mice in which an androstenedione supplement was converted to estrogen to stimulate tumor growth. When tumor volume was approximately 300 mm3, the animals were grouped (4 groups, each with n=20) for continued supplementation with androstenedione (Δ4A) only (control), Letrozole (an aromatase inhibitor) 10 μg/day + Δ4A, TAM 100 μg/day + Δ4A, or vehicle. Tumors were then retrieved at various time points during the development of hormone resistance. Tumor RNA samples were compared to reference RNA from Stratagene and incubated with 14K microarrays (Array-Ready Oligo Set, Qiagen). Expression results were analyzed with Genespring 6.1 (Silicon Genetics). Results: We have identified 15 TAM-resistant associated genes that are over-expressed by at least 2-fold, after controlling for genes associated with house-keeping function (vehicle and short term control), proliferation (freely growing tumors without TAM), and TAM inducible genes. They include; cystatin A, TGFbeta1-induced anti-apoptotic factor, cadherin1 E-cadherin, Snf2-related CBP activator protein, and chromatin-remodelling genes. At the meeting we will also present data on the expression changes seen in the Her-regulin family, cyclin family and MAP kinase genes during acquired TAM resistance. Patient biopsies are currently being collected and analyzed to validate these observations. Conclusions: Chromatin remodeling genes are over-expressed in acquired TAM-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis