Breast cancer has been the most commonly diagnosed female cancer in the UK since 1997, and is also the second leading cause of cancer death among women. In 2011, 49,936 women in the UK were diagnosed… read more
Breast cancer has been the most commonly diagnosed female cancer in the UK since 1997, and is also the second leading cause of cancer death among women. In 2011, 49,936 women in the UK were diagnosed with invasive breast cancer. Although 78% will survive 10yrs, metastasis significantly contributes to the approximately 11,000 deaths. A previous study from our group showed that, although rich in blood vasculature in breast cancer, lymphatic invasion (LI) is the predominant form (96%) of lymphovascular invasion (LVI), one of the initial steps of metastasis. Subsequent gene expression studies showed that down regulation of calpastatin (CAST) mRNA, and low levels of protein, significantly associated with LI. CAST is the endogenous inhibitor of calpain, a family of calcium-dependent cysteine proteases. Calpain-1 and -2 are ubiquitously expressed and recognized as important regulators of various cellular pathways such as proliferation, apoptosis, adhesion, and migration. Dysregulation of the calpain system, such as an imbalance between the level of calpain and calpastatin, is associated with a wide range of pathologies including muscular dystrophies, degenerative nerve diseases, myocardial infarction, diabetes, tumour invasion and metastasis. Although various CAST isoforms originate from a single gene the mechanism whereby each regulates calpain activity is largely unknown, with nothing previously examined regarding their ability to regulate LVI. This project seeks to determine the role that individual CAST isoforms play in regulating breast cancer cell migration and endothelial interactions to understand processes involved in regulating LVI.