PMCA2 Regulates HER2 Expression, Cell-Surface Localization and Signaling, and Promotes HER2- Mediated Breast Cancer

In the normal breast, PMCA2 transports calcium into milk. It is also upregulated in breast cancer cells and high tumor levels predict increased mortality in patients. In this study, we examined interactions between PMCA2 and HER2. We find that PMCA2 and a scaffolding protein, NHERF1, interact together with HER2 in specific membrane domains protruding from the surface of breast cancer cells. Knocking down PMCA2 or NHERF1 increases intracellular calcium and leads to the ubiquitination, endocytosis and degradation of HER2 after receptor activation. This is associated with reductions in HER2 expression and signaling. Manipulating PMCA2 levels regulates proliferation and apoptosis of breast cancer cells in vitro and knocking out PMCA2 dramatically inhibits the formation of hyperplasia and tumors in MMTV-Neu mice. Gene expression profiling was performed on control SKBR3 cells vs. PMCA2, NHERFR1 and HER2 knock down cells. Each group has 6 duplicates.