Abstract 1919: Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancers, is highly refractory to chemotherapy and has a high incidence of metastasis and tumor relapse. Targeted therapies for TNBC do not exist because this subtype lacks druggable hormone receptors and HER2 amplification or overexpression. Although Taxane-based chemotherapy is a standard of care for TNBC treatment, paclitaxel (Taxol)-induced cancer stem cell (CSC) enrichment presents a significant challenge to the success of breast cancer treatment. Thus, there is a critical need to understand the mechanisms by which chemotherapy induces CSC enrichment in residual tumors following anticancer therapies. Here we report that Taxol-induced enrichment for CSCs correlates well with a marked upregulation of Twist1 expression in human TNBC cells. Knockdown of Twist1 inhibits the clonogenic capacity of TNBC cells in vitro and TNBC tumorigenesis in vivo. Mammosphere formation assays indicate that silencing of Twist1 greatly diminishes the tumor sphere-forming potential of breast CSCs. Furthermore, limited dilution assays and stem cell xenotransplantation reveal that knockdown of Twist1 expression decreases the frequency of CSCs by 72-fold in human TNBC cells. More importantly, we show that silencing of Twist1 blocks Taxol-induced CSC enrichment in residual tumor cells that have survived drug treatment. Together, these results demonstrate a previously unrecognized role for Twist1 in mediating Taxol-induced CSC enrichment in residual tumors of human TNBC and suggest that targeted inhibition of the Twist1 signaling pathway may represent a novel therapeutic strategy to tackle therapy-induced CSC enrichment in breast cancer treatment. Citation Format: Aimin Yang, Xiaoyuan He, Bradley A. Schulte, Steven L. Carroll, Stephen P. Ethier, Gavin Y. Wang. Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2017-1919