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 conducted 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 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 with scrambled
siRNA-treated cells. In vivo data show 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, as shown 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 TNBCs.