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

// Kamila Bledzka 1 , Barbara Schiemann 2 , William P. Schiemann 2 , Paul Fox 3 , Edward F. Plow 1 and Khalid Sossey-Alaoui 1 1 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA 2 Case Comprehensive Cancer Center, Cleveland, Ohio, USA 3 Department of Cellular and Molecular Medicine, Cleveland, Ohio, USA Correspondence to: Khalid Sossey-Alaoui, email: sosseyk@ccf.org Keywords: WAVE3, CSCs, YB1, TNBC, chemoresistance Abbreviations: CSCs: Cancer stem cells; TNBC: Triple negative breast cancer; YB1: Y-box binding protein 1; ELDA: Extreme limited dilution assayReceived: July 22, 2017 Accepted: September 29, 2017 Published: October 24, 2017 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/ Cas9significantly 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 windowfor TNBCs treatment.