The role of tumor initiating cells in drug resistance of breast cancer: Implications for future therapeutic approaches.

The ability to prospectively isolate breast cancer cells that initiate tumors when transplanted orthotopically into immunocompromised mice has led to an explosion of work characterizing these cells and establishing ways to target them. Microarray studies screening for novel targets and chemical library screens for effective therapies have implicated signaling pathways, tumor-stromal interactions, miRNAs and possible even piwi-interacting (piRNAs) in the regulation of tumor initiating cell self-renewal. Potential targeting agents including the β-catenin inhibitor sulforaphane, AKT inhibitor perfosine, hedgehog inhibitor cyclopamine, stromal interaction inhibitor repertaxin, multidrug resistance pump poison dofequifar fumarate, as well as targeted the dual epidermal growth factor family inhibitor lapatinib and many more have all been found to have toxicity against purportedly chemotherapy resistant subpopulations of cancer cells often referred to as tumor initiating cells (TICs). Work using clinical samples is emerging and supports the hypothesis that neoadjuvant chemotherapy can enrich for TICs in residual disease, but strong correlation with long-term outcome is yet to be established. This paper reviews current attempts to targeting TICs and discusses the competing hypotheses to explain breast cancer recurrence and therapy resistance.