Protein Kinase C Alpha Destabilizes Adherens Junctions via p120-Catenin in Human Breast Cancer

Breast cancer is the most common type of cancer in women and progression to metastatic disease, often accompanied by drug resistance, greatly reduces a woman’s chance for survival. Metastasis is the spread and growth of cancer at a site that is discontinuous with the primary tumor. Elucidating the mechanisms that initiate and maintain a metastatic phenotype will likely lead to the identification of drug targets and biomarkers that will allow clinicians to prevent and treat metastases more successfully. Our lab has previously described the role of protein kinase C α (PKCα) in imparting a tamoxifen-resistant, hormone-independent phenotype in T47D:A18 breast cancer cells (T47D:A18/PKCα) in vitro and in vivo. PKCα is a serine/threonine kinase involved in signal relays following various stimuli resulting in survival, proliferation, anti-apoptosis, differentiation and cellular adhesion in various cellular contexts. The clinical relevance of PKCα in breast cancer was demonstrated by our laboratory as expression correlated with disease recurrence following tamoxifen treatment. In the current work, mining of breast cancer datasets showed that PKCα significantly ranked in the top genes overexpressed in those patients with worse clinical outcome defined as recurrence, metastasis and death. The current study was designed to explore the changes involved in the acquisition of a migratory and invasive phenotype in T47D:A18/PKCα cells, traits that can predict metastatic ability. We hypothesized that T47D:A18/PKCα cells had undergone an epithelial-mesenchymal transition (EMT) characterized by a loss of epithelial markers and the gain of mesenchymal markers and migratory and invasive abilities. We show that overexpression of PKCα induces these traits in breast cancer cells. Further, evaluation of the mechanism involved in this transition indicated a novel pathway mediated by PKCα-induced downregulation of p120-catenin adherens junction protein. PKCα seems to be the link between processes that confer poor prognosis in breast cancer including drug resistance, recurrence, metastasis and death. Therefore PKCα may prove to be a powerful biomarker that can be used to define endocrine-resistant breast cancers that may have an increased chance of developing metastasis. Further development of PKCα-specific therapeutics is also warranted based on the involvement of PKCα in these various stages of breast cancer progression.