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Uncovering Resistance Mechanisms of ErbB-2-targeted Therapies in Breast Cancer using Transcriptome Analysis

María Florencia Mercogliano

Weill Cornell Medical College

Breast cancer is the most frequent type of malignancies in women and the second most deadly one. It accounts for 500,000 deaths/year worldwide, and particularly in Argentina it is the first cause of cancer-related decease in women. The so-called ErbB-2-positive breast cancer subtype occurs in ~20% of invasive breast cancers, and it is associated with poor outcome. These patients are treated with trastuzumab, a monoclonal antibody against ErbB-2. However, the response rate is about 40-60% due to resistance at the beginning (de novo) or after months of treatment (acquired). We have demonstrated that a protein mediator, tumor necrosis factor alpha (TNF), plays a central role in limiting trastuzumab effectiveness. Using a trastuzumab-sensitive breast cancer cell line, genetically-engineered to synthesize TNF, we observed that it developed trastuzumab-resistant tumors with aggressive and invasive features. In addition, administration of TNF-blocking antibodies sensitizes de novo trastuzumab-resistant breast cancer to trastuzumab treatment in vivo and reduces tumor burden. Here we propose to dissect the resistance mechanisms of trastuzumab, and possibly to other ErbB-2-targeted therapies driven by TNF. To this end we will study the transcriptome (the complete set of RNA molecules in a cell) of ErbB-2-positive breast cancer cell line that synthesizes TNF, and compare it to the control cell line, under trastuzumab or control IgG treatment. We will analyze this data and obtain key pathways involved in trastuzumab resistance elicited by TNF. Then we will study candidate biomarkers of response to therapy in human breast cancer samples, and possible druggable targets to accomplish more promising therapies to prevent or overcome trastuzumab resistance. The administration of more effective treatments will hopefully contribute to the optimization of public health resources, especially limited in Argentina.

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