We are interested in understanding how constituents of the remodeled extracellular matrix and tumor stroma contribute resistance to therapy. ECM comprise the main ligands for integrins, which transmit extracellular cues to effect cell fate. We have investigated integrin signaling in pre-clinical models of breast cancer, showing its promise as a therapeutic target alone and with radiation therapy. In addition to the molecular aspects of ECM-induced signaling via integrins, recent developments point to the physical and mechanical aspects of the ECM and malignant stroma in cancer progression, and now, possibly resistance. We are interested in understanding how mechanical features of stroma may enhance resistance through integrin-dependent and independent pathways.