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

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.Additional Supporting Information may be found in the online version of this article.

Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses

“…More specifically, they also found that the level of TIAM-1 was significantly higher in tumor tissue from patients who died from breast cancer compared with those who survived. The finding that these GEFs are found differentially expressed between breast cancer and normal tissues supports other studies that also found expression changes of other Rho GTPase regulators in breast cancer [ 30 , 131 , 132 , 133 ]. Together, these data suggest that increased protein expression of certain Rho GTPases and Rho GTPase activators is correlated with worse patient prognosis, and that Rho GTPases may be promising prognostic tools in the clinic.…”

Regulation of cancer stem cells in triple negative breast cancer

“…Because they lack the expression of ER, a transcriptional repressor of PKD expression, TNBCs express high levels of PKD2 and PKD3 [79] . PKD3, especially, is associated with increased TNBC metastasis, proliferation, and stemness [78,[80][81][82] . Recently, Lieb et al [80] also demonstrated that upstream activation by Rho guanine nucleotide exchange factor 2 (GEF-H1) mediates PKD3 maintenance of TNBCSCs.…”

“…PKD3, especially, is associated with increased TNBC metastasis, proliferation, and stemness [78,[80][81][82] . Recently, Lieb et al [80] also demonstrated that upstream activation by Rho guanine nucleotide exchange factor 2 (GEF-H1) mediates PKD3 maintenance of TNBCSCs.…”

The oncogenic role of protein kinase D3 in cancer

“…Other researchers suggest that PRKD3 promotes the proliferation of breast cancer cells by activating the mitogen-activated protein kinase 3/MYC proto-oncogene axis or ELAV like RNA binding protein 1 [32,33]. The RhoGEF GRF-H1 is claimed to activate PRKD3 for the maintenance of TNBC stem cells [34]. Besides functioning in proliferation of breast cancer cells, PRKD3 also promotes the motility, spreading, and migration of breast cancer.…”