Protein Kinase C α Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells

Wai Leong Tam, Haihui Lu, Joyce Buikhuisen, Boon Seng Soh, Elgene Lim, Ferenc Reinhardt, Zhenhua Jeremy Wu, Jordan A. Krall, Brian Bierie, Wenjun Guo, Xi Chen, Xiaole Shirley Liu, Myles Brown, Bing Lim, Robert A. Weinberg

Research output: Contribution to journalArticle

182 Scopus citations

Abstract

The epithelial-mesenchymal transition program becomes activated during malignant progression and can enrich for cancer stem cells (CSCs). We report that inhibition of protein kinase C α (PKCα) specifically targets CSCs but has little effect on non-CSCs. The formation of CSCs from non-stem cells involves a shift from EGFR to PDGFR signaling and results in the PKCα-dependent activation of FRA1. We identified an AP-1 molecular switch in which c-FOS and FRA1 are preferentially utilized in non-CSCs and CSCs, respectively. PKCα and FRA1 expression is associated with the aggressive triple-negative breast cancers, and the depletion of FRA1 results in a mesenchymal-epithelial transition. Hence, identifying molecular features that shift between cell states can be exploited to target signaling components critical to CSCs.

Original languageEnglish (US)
Pages (from-to)347-364
Number of pages18
JournalCancer Cell
Volume24
Issue number3
DOIs
StatePublished - Sep 9 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Tam, W. L., Lu, H., Buikhuisen, J., Soh, B. S., Lim, E., Reinhardt, F., Wu, Z. J., Krall, J. A., Bierie, B., Guo, W., Chen, X., Liu, X. S., Brown, M., Lim, B., & Weinberg, R. A. (2013). Protein Kinase C α Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells. Cancer Cell, 24(3), 347-364. https://doi.org/10.1016/j.ccr.2013.08.005