P3-18-05: Triple-Negative Breast Cancer: Stem Cells, Cancer and New Treatment Strategy.

Abstract

Abstract Background: Women with triple negative breast cancer (TNBC) have a worse prognosis compared with other breast cancer subtypes. Hormonal or Herceptin-based therapies were found to be ineffective because of the loss of target receptors such as ER, PR and HER-2 amplification. TNBC has increased recurrence and poor survival, despite initial response to neoadjuvant chemotherapy. The aim of this study was to determine whether current drug treatment(s) eliminates bulk of tumor cells, but it has a minimal effect on cancer stem cells (CSCs) leading to tumor recurrence. Materials and Methods: Cancer stem cells were identified by ALDH-positive population by fluorescence-activated cell sorting. CSCs ability to form mammospheres, are generated in nonadherent and nondifferentiated conditions. Apoptosis was assessed using the Cell Death Detection ELISAPLUS kit. Xenograft tumor formation was evaluated using Nod/Scid mice. Cancer stem cell levels in human TNBC and ER+, PR+ and HER2− tumors were obtained by CD44+/ CD24low/− immunohistochemistry. Results: TNBC tumors express relatively higher levels of cancer stem cells compared to ER-positive, PR-positive and HER2−negative breast tumors. We studied the effects of PARP inhibitors (AZD2281 and BSI-201), paclitaxel, docetaxel, cisplatin and cisplatin plus TRAIL on CSCs derived from CRL-2335 and MDA-MB-468 TNBC cells in vitro. The in vitro data indicates that cisplatin plus TRIAL treatment was most effective in eliminating CSCs compared to PARP inhibitors, cisplatin, paclitaxel and docetaxel. Treatment with cisplatin plus TRAIL also inhibits Wnt-1 signaling and its downstream target, β-catenin, phospho β-catenin, cyclin D1, increased apoptosis, reduced proliferation and mammosphere formation. Inhibition of Wnt-1 by siRNA significantly reduced the ability of CSCs to form mammospheres compared to control. However, maximum effect was seen in cisplatin plus TRAIL treated cells. The combination of cisplatin/TRAIL also inhibited the growth of CRL-2335 Xenografts. Discussion: We demonstrate for the first time that cisplatin plus TRAIL is highly effective in reducing CSCs compared to PARP inhibitors, docetaxel or paclitaxel in TNBC cells in vitro. Inhibition of Wnt-1 signaling pathways by siRNA or cisplatin plus TRAIL reduces cell proliferation and increases apoptosis in CSCs. Taken together the data suggests that cisplatin plus TRAIL treatment has the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-05.