Background: The triple-negative breast cancer (TNBC) subtype of clinical breast cancer lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2). The TNBC subtype represents an aggressive cancer with high risk of fetal metastasis. Because of the lack of receptor expression, the therapeutic options for TNBC are restricted to conventional chemotherapy of cytotoxic anthracyclins, paclitaxels and cisplatin. Long-term chemotherapy is associated with intrinsic or acquired therapy resistance and emergence of chemo-resistant cancer initiating caner stem cell population that is endowed with cellular plasticity, epithelial-mesenchymal transition and high risk of metastatic progression. These limitations emphasize an unmet need to identify therapeutic alternatives. Natural products such as nutritional herbs, because of low systemic toxicity, documented human consumption and growth inhibitory efficacy in cancer stem cells, may represent testable alternatives. Bioactive agents present in nutritional herbs may provide novel drug candidates. 

Experimental Models: ER/PR/HER-2 negative MDA-MB-231 cells and doxorubicin resistant MDA-MB-231/DOX-R cells represent cellular models for TNBC and drug-resistant cancer stem cells, respectively.

Experimental Modulation: Treatment of the parental MDA-MB-231 cells with select nutritional herbs results in anti-proliferative effects associated with downregulated RB, RAS, PI3K and AKT signaling pathways. Pro-apoptotic effects of the nutritional herbs are associated with reciprocal modulation in anti-apoptotic BCL-2 and pro-apoptotic BAX expression. The MDA-MB-231/DOX-R cells exhibit increased tumor spheroid formation and upregulated expression of stem cell specific CD44 cell surface protein, and NANOG and OCT-4 nuclear transcription factors.

Conclusion: Collectively, this evidence validates facile experimental approaches to identify and prioritize novel drug candidates as testable alternatives against therapy resistant TNBC stem cell population. Future investigations utilizing patient-derived tumor samples may minimize extrapolation and facilitate clinical relevance and translatability of preclinical evidence. [Word Count: 280].