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.
Highlights
Metastatic breast cancer (BC) ranks 2nd as the cause of cancer-related death in women in the United States, accounting for more than 40,000 deaths annually [1]
This study demonstrates that WAVE3 regulates cancer stem cells (CSCs) maintenance and does so at least in part by controlling the translocation to the nucleus of the CSC-specific transcription factor Y-box-binding protein-1 (YB1)
This is the first study to show that WAVE3 influences CSC function, thereby providing a mechanism by which increased levels of WAVE3 in triplenegative breast cancers (TNBCs) correlates with resistance to therapy and poor prognosis [14, 23, 27], properties tightly linked to CSCs
Summary
Metastatic breast cancer (BC) ranks 2nd as the cause of cancer-related death in women in the United States, accounting for more than 40,000 deaths annually [1]. Tumors of the triple-negative BC (TNBC) subtype are especially lethal due to their highly metastatic behavior [9,10,11,12,13]. TNBCs do not express hormone receptors (ER-α and PR) and lack amplification at the ErbB2/HER2 locus [9,10,11,12,13]. These specific molecular characteristics of TNBCs have impeded the development of FDA-approved targeted therapies against this BC subtype. TNBCs are highly proficient in becoming chemoresistant and www.impactjournals.com/oncotarget undergoing disease recurrence through mechanisms that remain incompletely understood
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