Grant: Travel Awards - Institute Community Support

This project explores calpain as a novel therapeutic target in breast cancer. Calpain is an intracellular calcium regulated protease - a protein that cleaves other proteins. Calpain cleavage substrates include many of the same regulators of cellular proliferation, survival, migration and invasion that are targeted with cancer therapeutics, and thus cleavage of key signaling proteins by calpain may sensitize cancer cells to targeted therapeutic agents. In the current study, we use both in vitro and in vivo techniques to show that calpain expression modulates sensitivity to a specific targeted therapy called 17AAG, which targets the Hsp90 molecular chaperone responsible for stabilizing many kinases involved in these same signaling pathways. In vitro studies show that overexpressing calpain renders cells resistant to 17AAG whereas downregulating its expression or inhibiting its activity leads to increased cell death in both Her2+ and triple negative breast cancer cell lines. Mouse mammary fat pad engraftments with breast cancer cells expressing decreased calpain levels and treated with 17AAG developed tumors that were significantly smaller than either its untreated or wildtype counterparts. Furthermore, combined loss of calpain and 17AAG exposure also led to a decrease in migration, invasion, and metastasis. We show the loss of calpain expression downreglates expression of specific ABC transporters, modulating their ability to efflux specific drug targets, rendering cells more sensitive to these targets. This study provides rationale for the development of therapeutic calpain inhibitors for use in combination with new or existing breast cancer therapeutics.