Protein Kinase C Alpha Mediates FOXC2 Transcriptional Repression Of p120-Catenin In Human Breast Cancer

Breast cancer is the most commonly diagnosed malignancy in women worldwide. Despite recent advances in prevention, diagnosis, and treatment, metastasis remains a roadblock to successful treatment, accounting for up to 90% of breast cancer related death. At the molecular level, metastasis is often initiated by a phenomenon named the epithelial-mesenchymal transition (EMT). During this process, epithelial cancer cells lose cell-to-cell contacts and gain the ability to invade the basement membrane and surrounding tissues. The integrity of these intercellular contacts, namely adherens junctions (AJ), has been demonstrated to depend on the expression of E-cadherin at the cell membrane. Notably, we have discovered that down-regulation of p120-catenin by the transcriptional factor FOXC2 can cause E-cadherin loss. In addition, we have evidence to demonstrate PKCα as a novel positive regulator of FOXC2 expression. Knockdown of either PKCα or FOXC2 is sufficient to reduce their migration and invasion ability, which coincides with re-expression of p120-catenin and E-cadherin at the cell membrane. Our working model suggests that suppression of p120-catenin by PKCα and FOXC2 serves as a critical event in the dissolution of the AJ, which facilitates migration of breast cancer cells. More importantly, the hierarchical relationship between PKCα, FOXC2, and p120-catenin is particularly relevant in endocrine resistant breast cancer and triple negative breast cancer (TNBC), but not in endocrine-sensitive breast cancer. Expression of PKCα, FOXC2, and p120-catenin in clinical samples signify the TNBC subtype, as well as early relapse events in ER-positive patients. These findings provide some mechanistic insights on an alternative molecular pathway leading to breast cancer metastasis, and suggest new therapeutic targets to prevent metastasis in patients who no longer respond to tamoxifen and are TNBC.