Calpain-1 and Calpain-2 Promote HER2/NEU Tumorigenesis and Independently Promote Metastasis in Triple Negative Breast Cancer

Abstract

Calpains are a family of calcium activated cysteine proteases. Calpain-1 and calpain-2 are obligate heterodimers composed of isoform specific catalytic subunits (encoded by capn1 and capn2, respectively) coupled with the common, shared regulatory subunit calpain small subunit 1 (encoded by capns1). Here, we report a role for these calpains in promoting spontaneous tumor onset in a model of human HER2+ breast cancer, as well as a requirement for these calpains for tumor viability in an orthotopic engraftment model. Furthermore, we demonstrated that knockout of capns1 correlated with enhanced sensitivity to the chemotherapeutic doxorubicin, the EGFR/HER2 inhibitor lapatinib, and sustained MAPK signaling in response to EGF. In a model of triple-negative breast cancer we demonstrate that CRISPR/CAS9-mediated knockout of calpain-1 (capn1) or calpain-2 (capn2) independently attenuated metastatic colonization in vivo, and that knockout of either isoform was associated with attenuated production of MMP-9. Collectively, our results suggest a pro-tumorigenic role for calpain-1/2 in both HER2+ and triple-negative breast cancer, which provides preclinical evidence in support of combining calpain inhibitors with commonly used therapeutic drugs.