Secretory Pathway Calcium ATPases in Breast Cancer

Secretory Pathway Ca2+-ATPases (SPCA) are P-type pumps that localize to the Golgi and post-Golgi vesicular compartments into which they sequester Ca2+ and Mn2+ ions required for protein processing, glycosylation and sorting. There are two isoforms in human that play distinct roles in breast cancer, a leading cause of death in women worldwide. Previously, we showed that SPCA2, but not SPCA1, interacts with the Ca2+ channel Orai1 to initiate store-independent Ca2+ entry, which promotes tumorigenesis. We sought to understand the roles of SPCA1 and SPCA2 in breast cancer and how they correlate with the different subtypes and with epithelial-mesenchymal transition (EMT). SPCA2 expression is greatly amplified in luminal subtypes but has a lower expression in basal subtypes, with opposite expression patterns for SPCA1. We present analysis of patient survival and microarray data for both SPCA1 and SPCA2 expression, and evaluate isoform-specific roles in two different breast cancer cell lines, which represent epithelial (MCF7) and post-EMT (MDA-MB-231) subtypes. Using knockdown and overexpression approaches, we correlate isoform expression with cell proliferation, tumorsphere formation, and plasma membrane trafficking of a cell adhesion protein critical for tumorigenesis, E-cadherin. From these studies, we conclude that SPCA2 promotes oncogenesis by regulating E-cadherin and that SPCA2 down regulation may be critical for metastasis.