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The global profiling of differentially expressed genes in subtypes of clinical breast cancer identifies predic‐ tive and prognostic biomarkers for disease progression and rationalizes breast cancer subtype‐based treatment options. The expression status of hormone and growth factor recep‐ tors dictates the options for chemo‐endocrine and/or pathway selective small molecule inhibitor‐based treatments. Overall, these treatment options are associated with long‐term systemic toxicity and acquired tumor resistance, predominantly due to the emergence of drug‐resistant cancer stem cell population and due to therapy‐resistant disease progression. These limitations emphasize the identification of non‐toxic testable therapeutic alternatives for the efficacious targeting of breast cancer stem cells. The present review summarizes published evidence focused on i) developing cellular models for molecular subtypes of breast cancer; ii) isolating and characterizing drug‐resistant cancer stem cells from the developed models; and iii) identi‐ fying mechanistic leads for potential stem cell‐targeting lead compounds. Cellular models for Luminal A, human epidermal growth factor receptor‐2 (HER‐2) enriched and triple‐negative breast cancer subtypes represented the experimental models. Prototypic chemo‐endocrine therapeutic agents were used to select the drug‐resistant stem cell phenotype. The vitamin A derivative, all‐trans retinoic acid, and the rosemary terpenoid, carnosol, respectively representing a mechanistically distinct natural product and a potential bio‐active constituent of a nutritional herb provided stem cell‐selective lead compounds. The cellular models for Luminal A, HER‐2‐enriched and triple‐negative breast cancer subtypes exhibited growth inhibitory effects in response to treatment with prototypic chemo‐endocrine therapeutics, natural products and nutritional herbs. Drug‐resistant phenotypes exhibited an upregulated expression of stem cell‐specific cellular and molecular markers. Lead compounds induced the downregulated expression of the stem cell markers in drug‐resistant phenotypes. These data validate an experimental approach with which to identify potential non‐toxic natural products and nutritional herbs that may represent testable alternatives for the stem cell targeted therapy of breast cancer.

Stem cell targeted therapeutic approaches for molecular subtypes of clinical breast cancer (Review)