The WAVE3-YB1 interaction regulates cancer stem cells activity in breast cancer

Abstract

Resistance to therapy is the main cause of tumor recurrence and metastasis and cancer stem cells (CSCs) play a crucial role in this process, especially in triple-negative breast cancers (TNBCs). Unfortunately, no FDA-approved treatment is currently available for this subtype of BC, which explains the high rate of mortality in patients with TNBC tumors. WAVE3, a member of the WASP/WAVE actin-cytoskeleton remodeling family of protein, has been established as a major driver of tumor progression and metastasis of several solid tumors, including those originating in the breast. Our recently published studies found WAVE3 to mediate the process of chemoresistance in TNBCs. The molecular mechanisms whereby WAVE3 regulates chemoresistance in TNBC tumors remains largely unknown, as does the role of WAVE3 in CSC maintenance. Here we show that WAVE3 promotes CSC self-renewal and regulates transcription of CSC-specific genes, which, in part, provides a mechanistic explanation for the function of WAVE3 in chemoresistance in TNBCs. Our data show that WAVE3 is enriched in the CSC-subpopulation of TNBC cell lines. Knockout of WAVE3 via CRISPR/Cas9 significantly attenuates the CSC-subpopulation and inhibits transcription of CSC transcription factors. Mechanistically, we established a link between WAVE3 and the Y-box-binding protein-1 (YB1), a transcription factor and CSC-maintenance gene. Indeed, the interaction of WAVE3 with YB1 is required for YB1 translocation to the nucleus of cancer cells, and activation of transcription of CSC-specific genes. Our findings identify a new WAVE3/YB1 signaling axis that regulates the CSC-mediated resistance to therapy and opens a new therapeutic window for TNBCs treatment.

CRISPR/Cas9 for overcoming drug resistance in solid tumors

“…Disruption of WAVE3, a member of the WASP/WAVE actin-cytoskeleton remodeling family, substantially attenuated cancer stem cell (CSC) populations in TNBC cell lines through suppressing CSC self-renewal capacity and transcriptional regulation of CSC-specific genes. These results support the critical role of WAVE protein in TNBC chemoresistance [66]. CRISPRbased knockout of MAP3K1 in mutant PIK3CA breast cancer cell lines resulted in an increased proliferation rate and decreased sensitivity to an AKT inhibitor (AZD5363) through enhanced phosphorylation of AKT in vitro as well as in vivo [40].…”

MicroRNA‐93 targets WASF3 and functions as a metastasis suppressor in breast cancer

“…Because the results of in vitro analyses suggested that invasion abilities and CSC properties were suppressed by the overexpression of miR‐93, we used the TargetScan 6.2 algorithm (http://www.targetscan.org) to search for putative miR‐93 targets that play important roles in the regulation of CSC properties and cell invasion. The search identified the WASF3 ( WAVE3 ) gene as one of the promising candidates 28,29 . Importantly, WASF3 is an actin cytoskeleton remodeling protein, which often functions as an oncogene, and is established as a major driver of tumor progression, invasion (Figure and Table ), and metastasis of breast cancers, 9,29 and is a marker associated with worse patient prognosis 29,30 .…”

“…Importantly, WASF3 is an actin cytoskeleton remodeling protein, which often functions as an oncogene, and is established as a major driver of tumor progression, invasion (Figure and Table ), and metastasis of breast cancers, 9,29 and is a marker associated with worse patient prognosis 29,30 . In addition, WASF3 promotes tumor sphere formation and the expression of CSC‐related genes 28 . Within its 3′‐UTR, WASF3 carries 2 predicted 8‐mer miR‐93 target sites (2728‐2735 and 3889‐3896 of the ): the former is poorly conserved across mammalian species, and the latter is highly conserved across mammalian species (Figure 4A, 8mer in lower boxes).…”

Cooperative Effect of Oncogenic MET and PIK3CA in an HGF-Dominant Environment in Breast Cancer

“…By systematically analyzing oncogenic signaling, we demonstrated that concurrent expression of oncogenic MET and PIK3CA synergistically activates multiple oncogenic signals, including RAS-MEK-MAPK, STAT3, and PI3K-AKT pathways in an HGF-enriched environment, and further markedly increases activation of Y-box binding protein 1 (YB1) that induces progression and metastasis of different types of cancer through angiogenesis, resistance of cell death, tumor-promoting inflammation, and evasion of immune destruction (40)(41)(42). Targeting PI3K significantly inhibits the PI3K-AKT pathway, whereas targeting MET dramatically inhibits the MAPK pathway and also inhibits the PI3K-AKT pathway.…”