Evaluation of Subtype Specific Collagen Remodeling in Breast Cancer Progression

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Project Summary/Abstract Currently there are no available therapies designed to appropriately target the triple negative/basal breast cancer subtype (TNBC). Due to the risk of recurrence and metastasis following primary therapy, novel avenues of intervention must be pursued. The tumor matrix, the material cancer cells are grown on, modulates cellular proliferation and survival, however a link between a TNBC subtype specific extracellular matrix (ECM) and mechanisms of TNBC drug resistance has not yet been made. This proposal will identify novel mechanism of matrix induced drug resistance in TNBC. Using a combination of 3D in vitro screens, murine models of TNBC, and primary patient samples, Dr. Martin will interrogate novel matrix proteins (collagen IV, XII, and fibronectin) involved in TNBC drug resistance. The hypothesis of this proposals is: TNBC extracellular matrix enhances drug resistance through the induction of cellular dormancy. Dr. Martin will use in vitro 3D tumor models to screen the effects of matrix composition on induction of cellular dormancy and a cancer stem cell phenotype in TNBC. Furthermore Dr. Martin will determine how cancer cells grown on different matrix composites alter T-cell activation and proliferation, providing new insight on matrix induced immune evasion. These in vitro screens will be validated in vivo through the construction and evaluation of conditional knock out of matrix proteins (collagen IV, XII, fibronectin) in the mammary fat pad of transgenic murine models. Finally the clinical significant of this study will be verified through the interrogation and histological evaluation of matrix composition, immune infiltration, and occurrence of cell dormancy in a panel TNBC primary tumors. Dr. Martin will use proteomics to evaluate the matrix composition of primary TNBC and adjacent matched tissue and correlate these finding with observed immune infiltration. Additional histological evaluation and confirmation will also be performed. This will be investigated through the following specific aims: Specific Aim 1. Evaluate the effect of ECM composition on TNBC drug resistance. Specific Aim 2. Determine the translational relevance of subtype specific ECM composition.