CRP2, an innovative target to inhibit invadopodia activity and pro-metastatic MMP expression in breast cancer

Breast cancer is one of the most commonly diagnosed cancer types, with about 2.1 million new cases worldwide in 2018, constituting approximately 25% of all cancer diagnoses in women. It is also the leading cause of cancer death in over 100 countries (approximately 626,700 deaths in 2012). Despite these grim numbers, breast cancer is routinely over-diagnosed and over-treated in developing countries; however, differentiating invasive, life-threatening breast tumors from benign neoplasms with ahigh degree of sensitivity and accuracy is currently a difficult research question. It is with this pressing clinical need in mind that we are investigating the role of the actin cytoskeleton in breast cancer invasion and metastasis. We had previously identified cysteine-and glycine-rich protein 2 (CSRP2) as a novel and critical component of invadopodia, actin-rich, sub-cellular structures in cancer cells that facilitate their escape from the primary site and distant spread. We found that CSRP2 is an actin-bundling protein that localizes to the actinbackboneof these structures. Its levels are low in non-invasive epithelial breast cancer cell lines and much higher in invasive, mesenchymal lines. Loss of CSRP2 in theinvasive lines strongly decreased invadopodia formation, secretion of extracellular matrix-degrading proteinases known as MMPs, and cell invasion, as well as formation of distant metastases in mouse breast cancer models. High levels of CSRP2 expression in basal-like breast tumors is associated with a greater risk of metastasis in human breast cancer patients. We also made the preliminary observation that loss of CSRP2 in aggressive breast cancer cell lines significantly reduced expression of certain MMPs.