The GEF‐H1/PKD3 signaling pathway promotes the maintenance of triple‐negative breast cancer stem cells. Issue 12 (14th December 2019)

• Record Type: Journal Article
• Authors: Lieb, Wolfgang S.; Lungu, Cristiana; Tamas, Raluca; Berreth, Hannah; Rathert, Philipp; Storz, Peter; Olayioye, Monilola A.; Hausser, Angelika
• Is Part Of: International journal of cancer. Volume 146:Issue 12(2020)
• Page Start: 3423
• Page End: 3434
• Publication Date: 2019-12-14
• Subjects: cancer stem cells -- TNBC -- PKD3 -- paclitaxel -- ALDH; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32798
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? The serine‐threonine kinase PKD3 is upregulated in triple‐negative breast cancer (TNBC) and associated with cell proliferation and metastasis. The mechanisms underlying PKD3 pro‐oncogenic function remain unclear, however. Here, the authors reveal a critical role for PKD3 in the maintenance and propagation of TNBC stem cells in vitro and in vivo . The function of PKD3 in the maintenance of cancer stem cells requires upstream activation by GEF‐H1. Importantly, the PKD inhibitor CRT0066101 and paclitaxel synergistically decrease TNBC stem cell prevalence and tumor recurrence in vivo . The results provide a rationale for targeting PKD3 to eliminate the tumor‐initiating cell population in TNBC.