Exploring the effect of genetic calpain disruption on cell migration, invasion, drug sensitivity, and metastasis in triple negative breast cancer

Abstract

Triple-negative breast cancer is an aggressive subtype of breast cancer that is associated with high rates of metastasis, which remains incurable. Neoadjuvant chemotherapies, like paclitaxel, have been reported to promote spread to secondary sites. Calpains are a family of calcium-activated proteases that have emerged as a potential target in triple-negative breast cancer. Calpains cleave substrates involved in various cell signalling pathways associated with tumourigenesis and metastasis. Based on these established roles for calpain, I aimed to further characterise the effects of calpain knockout on migration, invasion, tumour growth, and paclitaxel-induced metastasis in a mouse model of triple-negative breast cancer. I also explored the role of collapsin response mediator protein 2, a calpain substrate and microtubule-binding protein, in paclitaxel treatment. I hypothesised that calpain-deficient cells would be less migratory, invasive, and metastatic than wildtype cells and that calpain knockout would disrupt neoadjuvant paclitaxel-induced metastasis. I also hypothesised that over-expression of collapsin response mediator protein 2, would synergise with calpain knockout to sensitise triple-negative breast cancer cells to paclitaxel and impede migration and invasion in vitro. By understanding calpain’s role in metastasis, we aim to improve the efficacy of existing chemotherapeutics by combining them with pharmacological calpain inhibitors, thus expediting the development of much needed therapies for triple-negative breast cancer.