Evaluation of a triple negative matrix signature in tumor progression and resistance

Abstract Currently there are no available therapies designed to appropriately target the triple negative/basal breast cancer subtype (TNBC) in Black patients. 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 many aspects of cancer including proliferation, morphology, motility, and survival; however, a link between the TNBC subtype specific extracellular matrix (ECM) and mechanisms of TNBC tumorigenesis, metastasis, and drug response has not yet been made. Currently the role for TNBC ECM mediated tumorigenesis and drug resistance is underdefined in African American patient populations due to a lack of pre-clinical models that recapitulate the African American TNBC ECM. The following specific aims are designed to test the overall hypothesis that the use of the TNBC ECM 3D models will provide 1) insight on key ECM proteins that regulate TNBC tumorigenesis pre- and post- treatment and 2) provide a novel means to understand TNBC ECM mediated response to therapy. Aim 1 will focus on the evaluation of TNBC ECM from pre- and post- chemotherapy treated tumors with the goal of understanding TNBC ECM mediated tumorigenesis and metastasis. Aim 2 will focus on the utility of using TNBC ECM for the interrogation of cellular response to therapy. This will be achieved through a combination of 3D in vitro screens and murine models of TNBC. In vitro 3D tumor models will be generated to screen the effects of TNBC ECM composition on the induction of genes associated with tumorigenesis and metastasis. Specifically, we will evaluate genes associated with a cancer stem-like phenotype, epithelial to mesenchymal transition, and cellular growth. These in vitro screens will be validated in vivo through the implantation of seeded 3D scaffolds in the mammary fat pad of SCID/Beige mice and subsequent evaluation of tumorigenesis and metastasis. Finally, the clinical significance of this study will determine if TNBC ECM derived from tumors pre- and post- treatment alters response to therapy. TNBC cells grown in our 3D systems will be evaluated for response to known standard of care therapies via cell survival and kinase activation assays. Findings from this study will provide insight on both molecular markers for patient prognosis and identify key matrix proteins as novel drug targets.