The WAVE3/β-Catenin oncogenic signaling regulates chemoresistance in triple negative breast cancer

Background: Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the United States and worldwide. Triple negative breast cancer (TNBC), which lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2, are especially lethal due to their highly metastatic behavior, propensity to recur rapidly, and for their resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC. Methods: The Cancer Genome Atlas (TCGA) dataset was used to study the expression of WAVE3 and β[1]Catenin in breast cancer tumors. Kaplan-Meir Plotter analysis was used to correlate expression of WAVE3 and β-Catenin with breast cancer patients’ survival probability. MTT assay was used to quantify cell survival. CRIPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-Catenin oncogenic signaling in TNB. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors. Results: Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor 3 growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression of β-Catenin. Most importantly, the combination of WAVE3-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo. Conclusion: We identified a novel WAVE3/β-Catenin oncogenic signaling axis that modulate chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.