In this study we use genetic manipulation of capns1 in HER2+ models of breast cancer to show that calpain-1 and/or calpain-2 are involved in but not required for spontaneous tumor formation in a transgenic mouse model of HER2/NEU-driven tumorigenesis; however, capns1 knockout in established carcinoma cells effectively blocked their tumor forming capability in an orthotopic engraftment model and enhanced in vitro sensitivity to doxorubicin and lapatinib. Here, CAPNS1 is linked to carcinoma.