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Progression of benign tumors to invasive, metastatic cancer is accompanied by the epithelial-to-mesenchymal transition (EMT), characterized by loss of the cell-adhesion protein E-cadherin. Although silencing mutations and transcriptional repression of the E-cadherin gene have been widely studied, not much is known about posttranslational regulation of E-cadherin in tumors. We show that E-cadherin is tightly coexpressed with the secretory pathway Ca2+-ATPase isoform 2, SPCA2 (ATP2C2), in breast tumors. Loss of SPCA2 impairs surface expression of E-cadherin and elicits mesenchymal gene expression through disruption of cell adhesion in tumorspheres and downstream Hippo-YAP signaling. Conversely, ectopic expression of SPCA2 in triple-negative breast cancer elevates baseline Ca2+ and YAP phosphorylation, enhances posttranslational expression of E-cadherin, and suppresses mesenchymal gene expression. Thus, loss of SPCA2 phenocopies loss of E-cadherin in the Hippo signaling pathway and EMT–MET transitions, consistent with a functional role for SPCA2 in E-cadherin biogenesis. Furthermore, we show that SPCA2 suppresses invasive phenotypes, including cell migration in vitro and tumor metastasis in vivo. Based on these findings, we propose that SPCA2 functions as a key regulator of EMT and may be a potential therapeutic target for treatment of metastatic cancer. Implications: Posttranslational control of E-cadherin and the Hippo pathway by calcium signaling regulates EMT in breast cancer cells.

Breast cancer is one of the most common forms of cancer in women, causing over 40,000 deaths per year. The major concern with breast cancer is its tendency to metastasize, preferentially, to the brain, bone and other areas of high physiological calcium. Calcium is a vital component of the breast, as mammary tissue has the ability to sequester and compartmentalize such calcium. During lactation, mammary cells are required to concentrate the 2mM blood concentration of milk into the 40-80mM concentration of calcium found in milk. This action requires a highly coordinated group of calcium channels and pumps to seize the calcium into intracellular storage compartments. We have shown in previous studies that SPCA2 is highly upregulated during lactation and tumorigenesis. Additional studies from others have shown that TRP channels are also upregulated in lactation and tumorigenesis. Here we show that this induction is due to the interaction of these two molecular components of calcium homeostasis in breast tissue.