Putative cancer-initiating stem cells in cell culture models for molecular subtypes of clinical breast cancer

Abstract

Abstract. Cancer-initiating stem cells (CISC) represent a minor subpopulation of heterogeneous breast cancer. CISC are responsible for the acquired resistance to conventional chemoendocrine therapy and eventual relapse observed in patients with breast cancer. Certain molecular subtypes of clinical breast cancer that exhibit differential expression of genes coding for hormone and growth factor receptors differ in their response to conventional chemoendocrine therapy and targeted therapeutic inhibitors. Thus, the development of reliable cell culture models for CISC may provide a valuable experimental approach for the study of stem cell-targeted therapy for the treatment of breast cancer. The present study utilized optimized cell culture systems as experimental models for different molecular subtypes of clinical breast cancer, including luminal A, human epidermal growth factor receptor (HER)-2-enriched and triple negative breast cancer. Biomarker end points, including control of homeostatic growth, cancer risk and drug resistance, were quantitatively analyzed in the selected models. The results of the analyses indicated that, compared with the non-tumorigenic controls, the cell models representing the aforementioned molecular subtypes of clinical breast cancer exhibited aberrant cell cycle progression, downregulated cellular apoptosis and loss of control of homeostatic growth, as evidenced by hyperproliferation. Additionally, these models displayed persistent cancer risk, as indicated by their high incidence and frequency of anchorage-independent (AI) colony formation in vitro and their tumor development capacity in vivo. Furthermore, in the presence of maximum cytostatic drug concentrations, the drug-resistant phenotypes isolated from the parental drug-sensitive cell lines representing luminal A, HER-2-enriched and triple negative breast cancer exhibited an 11.5, 5.0 and 6.2 fold increase in cell growth, and a 5.6, 5.4 and 4.4 fold increase in the number of AI colonies, respectively, compared with the drug-sensitive controls.Collectively, the data of the present study demonstrated the presence of putative CISC in these breast cancer models.

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

“…It occurs predominantly due to the emergence of drug-resistant stem cells (6,40,41). Data presented on the isolation and characterization of DOX-resistant triple negative MDA-MB-231 cells validate a potential model for stem cell-targeted therapy.…”

“…Human tissue-derived preclinical models may reduce extrapolation of evidence for clinically relevant translational potential (16,18,41). Current research directions have provided optimized human tissue-derived cell culture models for triple negative molecular subtype of clinical breast cancer that represent a clinically relevant experimental system.…”

“…Select nuclear transcription factors Oct-3/4, Klf4, Sox2 and c-Myc (Yamanaka factors) are expressed in cancer stem cells derived from multiple organ sites (38)(39)(40)(41)(42)(43). These transcription factors are also essential for the induction of pluripotent stem cells derived from adult somatic cells (44)(45)(46)(47).…”

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).…”

Involvement of breast cancer stem cells in tumor angiogenesis

“…Studies have shown that about 40% of BC patients have experienced recurrence, and about 60-70% of patients display distant metastasis (4). Like normal human organs, tumors have a small number of primitive stem cells that have high proliferation, self-renewal, and differentiation potential.…”