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.
Highlights
Despite improved early detection and the development of novel therapeutics, triple-negative breast cancer (TNBC) still is associated with a high mortality rate
When comparing MDA-MB-231 shPKD3_1 cells with shNon_CTRL cells, we observed that Protein kinase D3 (PKD3) depletion caused a significant decrease in aldehyde dehydrogenase 1 (ALDH) activity as measured by aldefluor assay (Fig. 1f ), which further substantiated a potential role of the kinase in stem cell regulation
PKD3-mediated TNBC stem cell regulation is dependent on GEF-H1 We recently reported that GEF-H1 is an upstream activator of protein kinase D (PKD) at the Golgi complex in HeLa cells[33] (Fig. 3a)
Summary
Despite improved early detection and the development of novel therapeutics, triple-negative breast cancer (TNBC) still is associated with a high mortality rate. PKD1 is the predominant isoform but its gene expression is suppressed during cancer progression by epigenetic silencing.[16] In TNBC, an isoform switch toward high PKD3 expression occurs, resulting from the lack of ER, a repressor of PKD3 gene expression.[17,18] Elevated PKD3 levels are associated with increased proliferation and cell motility, metastatic progression, as well as poor prognosis, supporting a pro-oncogenic role for PKD3 in TNBC.[17,19,20] molecular pathways controlling the activity of PKD3 and its precise prooncogenic function in TNBC have remained elusive
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