Genetic disruption of Capns1 impairs metastatic phenotypes in murine mammary carcinoma cells.

Calpains are a family of 15 calcium-activated cysteine proteases that have emerged as potential antimetastatic targets in breast cancer. Calpain-1 and calpain-2 are ubiquitously expressed heterodimers composed of unique catalytic subunits (encoded by Capn1 and Capn2 , respectively) and a common regulatory subunit (encoded by Capns1 ). Genetic disruption of Capns1 abolishes calpain-1 and calpain-2 activity. Using CRISPR-Cas9 mediated Capns1 knockout, we validated calpains-1/2 as promising therapeutic targets in a mouse model of mammary carcinoma. Capns1 knockout impaired cell invasion by 53 ± 10% in vitro and reduced lung metastasis by 68 ± 12% in an orthotopic engraftment mouse model.