Abstract
Abstract Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority that had a residual tumor had a relatively poor outcome. We have previously shown that cisplatin plus TRAIL treatment was most effective compared to PARP -inhibitors, pacliotaxol, dacelotaxol or cisplatin alone in TNBC cells. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 and MDA-MB-468 TNBC cells before and after treatment with cisplatin plus TRAIL. Gene expression prolife revealed that cisplatin plus TRAIL significantly inhibited major signaling pathways related with cancer stem cells (CSCs) such as Notch, Hedgehog, TGFβ and most of the Wnt/β-catenin signaling when compared with untreated control group. However, residual cells after cisplatin plus TRAIL treatment showed a significant increase in the expression of Frizzled 8 (FZD8 -one of the Wnt receptors) and c-Myc. In vivo, animal studies indicate that cisplatin plus TRAIL treatments predominantly eliminated non-cancer stem cells (non-CSCs), as demonstrated by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells that were stably transfected with dsRed. This led to CSCs enrichment in residual tumors, as confirmed by immunostaining for CSC markers. Increase in FZD8 and c-Myc expression was also observed in residual tumors following treatment with cisplatin and TRAIL. In this study, we have found that c-Myc overexpression increased FZD8 expression, and its downstream signaling and together protect the cells from drug mediated cell death compared to vector transfected cells. c-Myc over-expressing cells do not show increased mammosphere formation; the numbers of CSCs per mammosphere are much higher compared to vector transfected controls. CDK inhibitor (dinaciclib) enhanced the cell death in c-Myc over expressing non-CSCs with minimal effect on CSCs. Inhibition of c-Myc using siRNA reduced c-Myc, FZD-8 and CSCs and enhanced sensitivity of cells to cisplatin plus TRAIL. Taken together, our findings suggest that c-Myc may play a major role in mediating CSC survival and resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBC. Citation Format: Shuping Yin, Vino T. Cheriyan, Arun K. Rishi, Kaladhar B. Reddy. c-Myc and Frizzled 8 play a major role in the regulation of cancer stem cells and drug resistance in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2225. doi:10.1158/1538-7445.AM2015-2225
Published Version
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