Sensitivity of Breast Cancer Stem Cells to TRA-8 Anti-DR5 Monoclonal Antibody.

摘要

Basal-like breast cancers (BLBCs) generally become resistant to cytotoxic agents and resistance has been attributed to the presence of tumor initiating cancer stem cells (CSCs). Furthermore, LRP6/Wnt appears to play a crucial role in BLBC and CSC progression, and may represent an excellent therapeutic target. We have previously described that TRA-8, a monoclonal antibody specific to death receptor 5, kills both the CSCs and non-CSC population of BLBCs. This study examined two questions: whether niclosamide (an FDA approved antihelminthic, that inhibits Wnt/ -catenin signaling) is cytotoxic to BLBCs and its CSC population; and whether niclosamide in combination with TRA-8 produces synergistic cytotoxicity. We characterized non- adherent ALDH enriched (NAAE) cells as a CSC enriched population from BLBC cell lines. Both Adherent and NAAE cells from 2LMP, SUM159, HCC1187, HCC1143 cell lines and patient pleural effusion samples showed that niclosamide inhibited Wnt/ -catenin pathway activation, down regulated LRP6, and decreased downstream -catenin signaling. The combination of TRA-8 and niclosamide showed additive to synergistic cytotoxicity and further reduced Wnt/ -catenin activity. In vivo studies also showed that intraperitoneal administration of niclosamide in combination with TRA-8 suppressed growth of established 2LMP orthotopic tumor xenografts. Treatment with niclosamide in combination with TRA-8 may be an effective therapy against BLBC.