Growth inhibitory efficacy of natural products in a model for triple negative molecular subtype of clinical breast cancer

Abstract

Abstract. Global gene expression profiling identifies predictive and prognostic biomarkers and rationalizes breast cancer subtype-targeted treatment. The Anthracyclin/Taxol and survival pathway specific small molecular inhibitors, constitute current treatment options. These options are associated with acquired tumor resistance and emergence of drug-resistant cancer stem cells. Dietary supplements and constitutive bioactive phytochemicals with relatively low systemic toxicity may provide testable alternatives for current therapy. Human breast epithelial cell lines 184-B5 (non-tumorigenic triple negative cell type) and MDA-MB-231 (breast carcinoma derived triple negative cell type) were used as the experimental models. Putative cancer chemo-preventive natural products and their constitutive bioactive agents represented the test agents. Anchorage independent growth, cell cycle progression and cell apoptosis quantified the treatment efficacy. Compared to the 184-B5 cells, the MDA-MB-231 cells exhibited anchorage-independent growth indicative of persistent cancer risk. Additionally, the MDA-MB-231 cells exhibited hyper-proliferation, accelerated cell cycle progression and inhibited apoptosis indicative of loss of homeostatic growth control. The test agents inhibited anchorage-independent growth via cytostatic and pro-apoptotic effects. The triple negative carcinoma-derived Doxorubicin-resistant phenotype exhibited cancer stem cell markers, including tumor spheroid formation and expression of CD44, NANOG and c-Myc. These data identify clinically relevant mechanistic leads for the efficacy of natural products in the aggressive therapy-resistant breast cancer subtype and suggests a testable approach for cancer stem cell-targeted therapy.

Anti‑proliferative and pro‑apoptotic effects of rosemary and constituent terpenoids in a model for the HER‑2‑enriched molecular subtype of clinical breast cancer

“…Notably, tumorigenic potential and AI colony formation have been indicated to have a positive correlation for experimentally induced tumorigenic transformation in human mammary epithelial cells (2,19,21). Additionally, AI colony formation is detectable in cellular models for luminal A and triple negative molecular subtypes for clinical breast cancer (22,23). Collectively, these data provide evidence that AI colony formation represents an in vitro surrogate endpoint for tumorigenic transformation and an indicator for cancer risk; thus, these data indicate the loss of homeostatic control of proliferation and persistence of cancer risk.…”

Targeting drug resistant stem cells in a human epidermal growth factor receptor‑2‑enriched breast cancer model

“…The emergence of drug-resistant phenotypes, tumor spheroid formation and the increased expression of nuclear transcription factors have been demonstrated in stem cell models for select breast cancer subtypes (19)(20)(21). Furthermore, the nuclear transcription factors, Oct-4, Kruppel-like factor 4 (Klf-4), SOX-2 and c-Myc, represent essential components for induced pluripotent cell models developed from adult somatic cells (25)(26)(27).…”

“…an upregulated cellular expression of select nuclear transcription factors, including Oct-4, NANOG and c-Myc (19)(20)(21). Thus, the expression status of transcription factors represents quantitative molecular markers in the developed stem cell models.…”

Anti‑inflammatory drug resistance selects putative cancer stem cells in a cellular model for genetically predisposed colon cancer

“…It is noteworthy that drug-resistant cancer stem cells have been isolated and characterized from colon carcinoma-derived cell culture models (31)(32)(33) and from luminal A and triple-negative breast carcinoma-derived cell culture models (43,44).…”