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Targeting IKK in Basal-Like Breast Tumors as a Therapeutic Approach

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Annual rept. 1 Jun 2009-31 May 2010

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Specifically, our hypothesis is that IKK and a form of NF-kappa B are activated in certain breast tumors including the majority of basal-like tumors and in Her2 cancers, leading to the expression of genes which promote oncogenesis and which lead to resistance to therapy. Additionally, we hypothesize that these tumors will respond to inhibitors of this pathway, either alone or in combination with chemotherapy. Based on our findings, we hypothesize that IKKNF-kappa B and Bcl2A1 a key gene regulated by NF-kappa B that is found upregulated in basal-like breast cancer are key determinants of cancer therapy resistance in certain breast tumors. In a new direction, we propose that the IKKNF- kappa B pathway drives invasion and proliferation of Her2 breast cancer. Our aims are to i Generate a tumor bank archive for the analysis of NF-kappa BIKK activation and associated gene expression, and correlate the findings derived from this analysis to breast tumor subtypes, ii Determine the mechanism of activation of Bcl2A1 and other NF-kappa B-dependent genes in basal-like cells identify signaling components required for NF-kappa B activation in basal-like cancer cells examine inhibitors of the NF-kappa BIKK pathway in vitro, and iii Characterize animal models of breast cancer for activation of NF-kappa B and for potential therapeutic responses to NF-kappa B inhibitors. In new directions, characterize the role of NF-kappa B downstream of Her2 in breast cancer, determine if Parp1 is a positive regulator of NF-kappa B in basal-like breast cancer and analyze effects of Parp inhibitors, and study tumor breast tumor initiating cells for activation of NF-kappa B.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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