Reduced tumorigenicity and drug resistance through the downregulation of octamer-binding protein 4 and Nanog transcriptional factor expression in human breast stem cells

Abstract

Breast cancer is the most common type of malignancy among females. Previous studies examining breast cancer tissue have demonstrated the presence of stem cells, and have detected octamer-binding protein 4 (Oct4) and Nanog transcription factor expression. In the present study, breast cancer stem cells (CSCs) were isolated and enriched from MDA-MB-231 breast cancer cell lines, and were defined as MDA-MB-231 stem cells using flow cytometry. The expression of Oct4 and Nanog in breast CSCs were detected by quantitative polymerase chain reaction and western blotting. RNA interference (RNAi) was used in order to downregulate the expression of Oct4 and Nanog. Drug resistance and tumor-initiating capability following in vivo injection of MDA-MB-231 stem cells transduced with negative RNAi, Oct4 RNAi and Nanog RNAi were compared with that of MDA-MB-231 stem cells without siRNA transfection as a control group. In addition the capability of MDA-MB-231 breast cancer cells to initiate tumor formation in mice was compared with that of MDA-MB-231 stem cells. A paclitaxel inhibition test was also conducted in order to detect resistance of MDA-MB-231 breast cancer stem cells to this treatment. The MDA-MB-231 stem cells were revealed to exhibit elevated percentages of the cluster of differentiation (CD)44+CD24−/low subset, high tumorigenicity and resistance to chemotherapy, all of which are characteristic stem cell properties. In addition, the MDA-MB-231 stem cells were more tumorigenic in vivo. Furthermore, the breast CSCs also expressed high levels of the Oct4 and Nanog transcription factors. Therefore, downregulation of Oct4 or Nanog expression may reduce chemotherapeutic drug resistance and tumorigenicity in breast CSCs. In conclusion, Oct4 and Nanog expression may be a key factor in the development of resistance to chemotherapy and tumor growth of breast CSCs. This finding indicates that Oct4 or Nanog-targeted therapy may be a promising means of overcoming resistance to chemotherapy and inhibiting tumor growth in breast cancer treatment.

Gene of the month:NANOG

“…Recent studies have shown that NANOG is highly expressed in the majority of breast tumours in comparison with normal tissues, and its expression has been associated with CSC-like properties,22 tumour aggressiveness17 and resistance to hormonal20 and chemotherapeutic agents 23. Furthermore, patients with stronger expression of NANOG have reduced disease-free and overall survival rates 20…”

“…Their coexpression was associated with lymph-node metastasis, mesenchymal marker expression and increased invasiveness of CSCs. Therefore, both may be useful biomarkers of early breast cancer24 and valuable targets for anticancer agents to inhibit tumour development and overcome resistance to chemotherapeutics 23…”

The expression of the embryonic gene Cripto‐1 is regulated by OCT4 in human embryonal carcinoma NCCIT cells

“…OCT4, expressed in both ES and EC cells, is tightly regulated to maintain the characteristics of pluripotent stem cells, as either high or low expression may induce differentiation [5,[7][8][9]. OCT4 is also expressed in a variety of solid tumors as well as in GCTs and is involved in tumorigenesis of cancer stem cells [10][11][12][13][14][15][16]. Therefore, deregulation and dysfunction of OCT4 may affect its oncogenic potential in a variety of cancers.…”

Myrtucommulone-A treatment decreases pluripotency- and multipotency-associated marker expression in bladder cancer cell line HTB-9

“…Increases in the expression of stem-ness markers, including NANOG, LIN28A and surface markers CD44 and CD90, were shown to play a critical role in chemoresistance to cisplatin, doxorubicin, docetaxel, 5-fluorouracil and carboplatin [46]. The therapies focused on inhibiting self-renewal of cancer stem cells, inducing their differentiation or targeting their cell-surface molecular markers [15,47,48]. However, treatment strategies with existing anti-cancer agents like cisplatin, oxaliplatin and 5-fluorouracil were reported to enhance cell viability and promote the self-renewal and survival of cancer stem cells in different cancer models [49][50][51].…”