Summary
Progression of benign tumors to invasive, metastatic cancer requires loss of the cell-adhesion protein E-cadherin. Although intensive efforts have focused on gene repression and silencing mutations, much less is known about posttranslational control of E-cadherin expression in cancer. SPCA2 is a secretory pathway Ca2+-ATPase that is down-regulated in metastatic breast cancer. We show that SPCA2 is tightly co-expressed with epithelial signature genes and required for E-cadherin biogenesis and cell surface expression. Unexpectedly, this function is uncoupled from Ca2+ pumping and mediated by binding to E-cadherin. Loss of SPCA2 is sufficient to disrupt cell-cell adhesion in tumorspheres and elicit mesenchymal gene expression through Hippo-YAP signaling. These findings point to a causal link between low SPCA2 levels and the epithelial-mesenchymal transition required for breast cancer metastasis.
Highlights
SPCA2 is an epithelial marker transcriptionally linked to E-cadherin expression
Loss of SPCA2 impairs E-cadherin biogenesis independent of Ca2+ pump activity
SPCA2 is required for tumorsphere formation and Hippo-YAP signaling to antagonize epithelial-mesenchymal transition
Down-regulation of SPCA2 in metastatic cancers may contribute to malignancy
Footnotes
↵1 Co-First Authors