Abstract 241: Tumor initiating cells and FZD8 play a major role in drugresistance and tumor progression in triple negative breast cancer.

Abstract

Abstract Triple-negative breast cancer (TNBC) is usually associated with poor outcome in part due to lack of benefit from targeted therapy. Previous studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women with TNBC; in contrast, the majority who had a residual tumor after treatment had a relatively poor outcome. In order to identify the mechanism by which residual cancer cells survive chemotherapy, we performed gene expression profile using CRL2335 TNBC cell line before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of the Wnt receptors, and its downstream targets LEF1 and TCF in residual tumor cells after treatment with cisplatin plus TRAIL compared with untreated controls. Inhibition of FZD8 by siRNA in the presence of cisplatin plus TRAIL reduced β-catenin and survivin levels, and increased apoptosis compared to scrambled siRNA-treated cells. In vivo, data demonstrate that cisplatin plus TRAIL treatment, significantly reduces tumor volume in nod/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non-tumor initiating cells (non-TICs), as demonstrated by whole-body fluorescent imaging of mice injected with mammosphere-forming cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt-signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBC. Citation Format: Kaladhar B. Reddy, Shuping Yin, R. Bonfil Daniel, Sanjeev Banerjee, Fazlul Sarkar, Seema Sethi. Tumor initiating cells and FZD8 play a major role in drugresistance and tumor progression in triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 241. doi:10.1158/1538-7445.AM2013-241