Tumor Initiating Cells and FZD8 play a major role in drug resistance in Triple- Negative Breast Cancer
Menée in vitro et in vivo, cette étude identifie des mécanismes justifiant l'intérêt de cibler la signalisation Wnt, via l'un de ses récepteurs FZD8, pour surmonter une résistance au cisplatine dans le traitement d'un cancer du sein triplement négatif
Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of Wnt receptors, and its downstream targets LEF1 and TCF in residual CRL2335 tumor cells after treatment with cisplatin plus TRAIL. Increased FZD8 levels were further confirmed in other TNBC breast carcinoma cell lines. Inhibition of FZD8 by siRNA in CRL2335 cells 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 CRL2335 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.
http://mct.aacrjournals.org/content/early/2013/02/27/1535-7163.MCT-12-1090.abstract