Type I gamma phosphatidylinositol phosphate kinase modulates invasion and proliferation and its expression correlates with poor prognosis in breast cancer

Introduction: The loss of E-cadherin based cell-cell contacts and tumor cell migration to the vasculature and lymphatic system are hallmarks of metastasis of epithelial cancers. Type I gamma phosphatidylinositol phosphate kinase (PIPKI gamma), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PI4,5P(2)) a lipid messenger and precursor to many additional second messengers, was found to regulate E-cadherin cell-cell contacts and growth factor-stimulated directional cell migration, indicating that PIPKI gamma regulates key steps in metastasis. Here, we assess the expression of PIPKI gamma in breast cancers and have shown that expression correlated with disease progression and outcome. Methods: Using a tissue microarray, we analyzed 438 breast carcinomas for the levels of PIPKI gamma and investigated the correlation of PIPKI gamma expression with patient survival via Kaplan-Meier survival analysis. Moreover, via knockdown of the expression of PIPKI gamma in cultured breast cancer cells with siRNA, the roles of PIPKI gamma in breast cancer migration, invasion, and proliferation were examined. Results: Tissue microarray data shows that similar to 18% of the cohort immunostained showed high expression of PIPKI gamma. The Kaplan-Meier survival analysis revealed a significant inverse correlation between strong PIPKI gamma expression and overall patient survival. Expression of PIPKI gamma correlated positively with epidermal growth factor receptor (EGFR) expression, which regulates breast cancer progression and metastasis. In cultured breast cancer cells, PIPKI gamma is required for growth factor stimulated migration, invasion, and proliferation of cells. Conclusions: The results reveal a significant correlation between PIPKI gamma expression and the progression of breast cancer. This is consistent with PIPKI gamma's role in breast cancer cell migration, invasion, and proliferation.