Evaluating CD44-EZRIN Interactions in Triple-Negative Breast Cancer: Tumourigenesis and Drug Resistance
breast cancer , metastasis , drug resistance , Ezrin , CD44 , Protein-Protein Interaction , Triple-Negative Breast Cancer , Mouse Models
When breast cancer is detected at an early localized stage, surgery is often successful in achieving long term survival. However, when breast cancer becomes invasive and progresses to metastatic disease, surgery followed by adjuvant therapies is required, and many patients fail to respond or relapse with treatment resistant metastatic disease. The CD44 cell adhesion molecule and the Ezrin cytoskeletal adaptor protein have emerged as potential drivers of metastasis and drug resistance in cancers of the breast and other organs. Their known ability to physically interact, and their overlapping chemoresistance and metastasis promoting properties suggest they cooperate mechanistically to drive these processes. To study this, we genetically manipulated Ezrin and CD44 in the engraftable MDA-MB-231 triple-negative breast cancer cell line model. We show that CD44 and Ezrin each play important roles in regulating cancer cell associated processes in vitro such as cell adhesion, clonogenic potential, directional migration, and sensitivity to chemotherapies, as well as in vivo metastatic potential. Using co-immunoprecipitation assays and a split luciferase protein-protein interaction biosensor, we explored the effect of engineered amino acid substitutions in CD44 and Ezrin on their molecular interactions to set the stage for future investigations into the functional consequences of targeting this CD44-Ezrin interaction and developing small molecule inhibitors. Our findings suggest that therapeutic strategies designed to interfere with Ezrin-CD44 interactions may sensitize aggressive breast cancers to chemotherapies and other targeted agents and attenuate their metastatic behaviour.