The CD44(hi) compartment in human breast cancer is enriched in tumor-initiating cells; however the functional heterogeneity within this subpopulation remains poorly defined. We used a triple-negative breast cancer cell line with a known bi-lineage phenotype to isolate and clone CD44(hi) single-cells that exhibited mesenchymal/Basal B and luminal/Basal A features, respectively. Herein we demonstrate in this and other triple-negative breast cancer cell lines that rather than CD44(hi)/CD24(-) mesenchymal-like Basal B cells, the CD44(hi)/CD24(lo) epithelioid Basal A cells retained classical cancer stem cell features such as tumor-initiating capacity in vivo, mammosphere formation and resistance to standard chemotherapy. This complements previous findings using oncogene-transformed normal mammary cells showing that only cell clones with a mesenchymal phenotype exhibit cancer stem cell features. Further, we performed comparative quantitative proteomic and gene array analyses of these cells and identified potential novel markers of breast cancer cells with tumor-initiating features, such as LSR, RAB25, S100A14 and MUC1, as well as a novel 31-gene signature capable of predicting distant metastasis in cohorts of estrogen receptor-negative human breast cancers. These findings strongly favor functional heterogeneity in the breast cancer cell compartment and hold promise for further refinements of prognostic marker profiling. Our work confirms that, in addition to cancer stem cells with mesenchymal-like morphology, those tumor-initiating cells with epithelial-like morphology, should also be the focus of drug development.