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

Abstract

Abstract : Basal-Like Breast Cancer (BLBC) accounts for 13% of all breast carcinomas (1). It is characterized by a unique mRNA profile with CK5/6 expression, inactivation of BRCA1 and lack of estrogen receptor and HER-2 amplification (1-3). BLBC is considered one of the most aggressive, metastatic, and chemoresistant breast cancer subtypes (4). Its poor prognosis is linked to enrichment for tumor initiating cancer stem cells (CSC) (5). The Cancer Stem Cell Model hypothesizes that tumors, similar to normal tissue, are organized in a cellular hierarchy, with CSC, as the initiating cells with potentially limitless proliferation abilities (6). The more differentiated descendants, which account for the majority of the tumor population, may also be able to proliferate, but regenerative ability is limited (6). Traditional chemotherapy agents target these differentiated cells, but unfortunately fail to kill the stem cell progenitor population (7). The chemoresistant stem cells are thought to be responsible for recurrence and metastasis of many tumor types (7). Several investigators have shown that BLBC cell lines and patient samples contain a subpopulation of breast cancer stem cells (BrCSC) (8, 9). These BrCSC are identified based on their enhanced tumorigenicity, tumorsphere forming ability, expression of CD44+/CD24-, elevated enzymatic activity of aldehyde dehydrogenase (ALDH), and dysregulation of self-renewing pathways, including Wnt, Hedgehog, and Notch signaling (10, 11). BrCSC also overexpress ABC efflux transporters, detoxification enzymes, and have slower turnover rate that make this sub-population likely to become resistant to chemotherapy (12, 13). Thus an effective BLBC therapeutic strategy must kill these propagating and chemoresistant BrCSC in addition to the proliferating non-stem cell cancer population (14).