Natural Bioactive Agents: Testable Stem Cell-Targeting Alternatives for Therapy-Resistant Breast Cancer

Long-term treatment options for conventional chemo-endocrine therapy and molecular-pathway-based targeted therapy are associated with acquired therapy resistance and the emergence of drug-resistant cancer-initiating stem cell populations, leading to the progression of metastatic disease. These treatment options are based on the expression status of estrogen receptor-α (ER-α), progesterone receptor (PR) hormone receptors, and/or of human epidermal growth factor receptor-2 (HER-2). The breast cancer subtypes Luminal A, Luminal B, and HER-2-enriched express hormone/growth factor receptors and exhibit a favorable response to hormone receptor modulators and growth factor receptor antagonists. The triple-negative breast cancer subtype lacks the expression of hormone/growth factor receptors and responds only to cytotoxic conventional chemotherapy. The clinical limitations, due to the modest therapeutic responses of chemo-resistant cancer-initiating stem cells, emphasize the need for the identification of stem cells targeting testable alternatives for therapy-resistant breast cancer. Developed drug-resistant stem cell models exhibit upregulated expression of select cellular biomarker tumor spheroid (TS) formations and cluster of differentiation44 (CD44), DNA-binding protein (NANOG), and octamer-binding protein-4 (OCT-4) molecular biomarkers that represent novel experimentally modifiable quantitative endpoints. Naturally occurring dietary phytochemicals and nutritional herbs containing polyphenols, flavones, terpenes, saponins, lignans, and tannins have documented human consumption, lack systemic toxicity, lack phenotypic drug resistance, and exhibit preclinical efficacy. Constituent bioactive agents may provide testable stem cell-targeting alternatives. The present report provides an overview of (i) clinically relevant cellular models and drug-resistant cancer stem cell models for breast cancer subtypes, (ii) evidence for preclinical efficacy and mechanistic leads for natural phytochemicals and nutritional herbs, and (iii) the potential for the stem cell-targeting efficacy of natural bioactive agents as testable drug candidates for therapy-resistant breast cancer.