A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells

Donna K. Dang, Monish Ram Makena, José P. Llongueras, Hari Prasad, Myungjun Ko, Manuj Bandral, Rajini Rao

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1735-1747
Number of pages13
JournalMolecular cancer research : MCR
Volume17
Issue number8
DOIs
StatePublished - Aug 1 2019

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Epithelial-Mesenchymal Transition
Calcium-Transporting ATPases
Cadherins
Breast Neoplasms
Neoplasms
Cell Adhesion
Triple Negative Breast Neoplasms
Gene Expression
Calcium Signaling
Secretory Pathway
Cell Movement
Protein Isoforms
Phosphorylation
Neoplasm Metastasis
Phenotype
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells. / Dang, Donna K.; Makena, Monish Ram; Llongueras, José P.; Prasad, Hari; Ko, Myungjun; Bandral, Manuj; Rao, Rajini.

In: Molecular cancer research : MCR, Vol. 17, No. 8, 01.08.2019, p. 1735-1747.

Research output: Contribution to journalArticle

Dang, Donna K. ; Makena, Monish Ram ; Llongueras, José P. ; Prasad, Hari ; Ko, Myungjun ; Bandral, Manuj ; Rao, Rajini. / A Ca2+-ATPase Regulates E-cadherin Biogenesis and Epithelial-Mesenchymal Transition in Breast Cancer Cells. In: Molecular cancer research : MCR. 2019 ; Vol. 17, No. 8. pp. 1735-1747.
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