Mechanism of Aromatase Inhibitor Resistance

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DESCRIPTION (provided by applicant): Clinical trials have highlighted the importance of aromatase inhibitors in the treatment of breast cancer. Yet, as with all prolonged drug therapy, resistance does develop via a currently unknown mechanism. This lab hypothesizes that resistance to aromatase inhibitors does entail an alternate signaling pathway that allows cells to adapt to the presence of the inhibitor, but still undergo normal cell proliferation. To address this question, this lab has generated MCF-7aro (aromatase overexpressed) breast cancer cell lines that are resistant to aromatase inhibitors and the anti-estrogen tamoxifen. 1. To investigate candidate genes involved in resistance to aromatase inhibitors, this lab intends to perform microarray analysis of the MCF-7aro resistant cell lines. 2. To better understand how genes identified by microarray are involved in resistance to aromatase inhibitors, further mechanistic studies will be done, by gene overexpression or knockdown in cell culture and analysis of activated signal transduction pathways. This project has critical clinical implications in that the effective treatment of breast carcinomas does rely on understanding drug-resistance at the molecular level.