The GEF-H1/PKD3 signaling pathway promotes the maintenance of triple-negative breast cancer stem cells

Wolfgang S. Lieb, Cristiana Lungu, Raluca Tamas, Hannah Berreth, Philipp Rathert, Peter Storz, Monilola A. Olayioye, Angelika Hausser

Research output: Contribution to journalArticle

Abstract

Protein kinase D3 (PKD3) is upregulated in triple-negative breast cancer (TNBC) and associated with cell proliferation and metastasis development but its precise pro-oncogenic function is unknown. Here we show that PKD3 is required for the maintenance of the TNBC stem cell population. The depletion of PKD3 in MDA-MB-231 cells reduced the cancer stem cell frequency in vitro and tumor initiation potential in vivo. We further provide evidence that the RhoGEF GEF-H1 is upstream of PKD3 activation in TNBC stem cells. Most importantly, pharmacological PKD inhibition in combination with paclitaxel synergistically decreased oncosphere and colony formation efficiency in vitro and tumor recurrence in vivo. Based on our results we propose that targeting the GEF-H1/PKD3 signaling pathway in combination with chemotherapy might provide an effective therapeutic option for TNBC.

Original languageEnglish (US)
Pages (from-to)3423-3434
Number of pages12
JournalInternational Journal of Cancer
Volume146
Issue number12
DOIs
StatePublished - Jun 15 2020

Keywords

  • ALDH
  • cancer stem cells
  • paclitaxel
  • PKD3
  • TNBC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Lieb, W. S., Lungu, C., Tamas, R., Berreth, H., Rathert, P., Storz, P., Olayioye, M. A., & Hausser, A. (2020). The GEF-H1/PKD3 signaling pathway promotes the maintenance of triple-negative breast cancer stem cells. International Journal of Cancer, 146(12), 3423-3434. https://doi.org/10.1002/ijc.32798