Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

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 DESCRIPTION (provided by applicant): Triple Negative Breast Cancers (TNBC), if considered its own disease, would rank as the fifth or sixth leading cause of cancer deaths in women in the USA. The only treatment option for these patients is multi-agent chemotherapy, and TNBC tumors are highly variable in terms of their chemotherapy sensitivity. TNBC is also known to be biologically heterogeneous, with multiple possible subtypes present. We hypothesize that much of this apparent heterogeneity actually represents cellular plasticity, and that some forms of heterogeneity can actual morph from one form into another; for example, in vitro and in vivo results show that within basal-like cell lines, claudin-low-like cells exist and can inter-convert nto the more differentiated basal-like epithelial state. We propose to test this plasticity hypothesis using in vivo models by identifying some of the genetic determinants that drive cells into the basal-like state (which is more chemotherapy sensitive), and that maintain TICs in basal-like cancers using both genetically engineered mouse (GEM) and patient derived xenograft (PDX) models. In addition, we will compare the response to standard of care therapies in the primary tumor versus a metastatic site (i.e. lung), and evaluate changes in TICs using unique signaling pathway-based reporters.