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The GEF‐H1/PKD3 signaling pathway promotes the maintenance of triple‐negative breast cancer stem cells
Author(s) -
Lieb Wolfgang S.,
Lungu Cristiana,
Tamas Raluca,
Berreth Hannah,
Rathert Philipp,
Storz Peter,
Olayioye Monilola A.,
Hausser Angelika
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32798
Subject(s) - triple negative breast cancer , cancer research , stem cell , cancer stem cell , biology , metastasis , breast cancer , cancer , microbiology and biotechnology , genetics
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.