Journal of Cancer Research and Treatment
ISSN (Print): 2374-1996 ISSN (Online): 2374-2003 Website: Editor-in-chief: Jean Rommelaere
Open Access
Journal Browser
Journal of Cancer Research and Treatment. 2019, 7(2), 36-43
DOI: 10.12691/jcrt-7-2-1
Open AccessArticle

Gene Expression of OCT4 and NANOG Correlated with Advanced Stage and Worse Survival in Breast Cancer Patients

Fawziya A. R Ibrahim1, , Shaymaa E. El Feky2, Kadhim K. Kadhim3, Nadia A. Abd El Moneim4, Mohammad A. Ahmmad5 and Salah A. Sheweita3

1Applied Medical Chemistry Department, Medical Research Institute, University of Alexandria, Alexandria, Egypt

2Radiation Sciences Department, Medical Research Institute, University of Alexandria, Alexandria, Egypt

3Biotechnology Department, Institute of Graduate Studies and Research, University of Alexandria, Alexandria, Egypt

4Cancer Management and Research Department, Medical Research Institute, University of Alexandria, Alexandria, Egypt

5Clinical Pathology Department, Medical Military Academy, Alexandria, Egypt

Pub. Date: October 24, 2019

Cite this paper:
Fawziya A. R Ibrahim, Shaymaa E. El Feky, Kadhim K. Kadhim, Nadia A. Abd El Moneim, Mohammad A. Ahmmad and Salah A. Sheweita. Gene Expression of OCT4 and NANOG Correlated with Advanced Stage and Worse Survival in Breast Cancer Patients. Journal of Cancer Research and Treatment. 2019; 7(2):36-43. doi: 10.12691/jcrt-7-2-1


The present study aimed to show the correlation between expression of cancer stem cell markers (OCT4 and NANOG) with both clinicopathological features and survival of breast cancer (BC) patients. Methods: The gene expressions of OCT4 and NANOG were quantified using real time polymerase chain reaction, clinicopathological data have been collected from patients' data records and patients were followed-up with a median duration of 110 months. Results: OCT4 (p<0.001), and NANOG (p<0.001) expressions were upregulated in BC tissues compared to adjacent normal tissues. OCT4 and NANOG were associated with poor histological grade (p=0.029, 0.025) and advanced clinical stage (p=0.001, 0.042 respectively). OCT4 alone showed a significant association with lymph nodes involvement (p=0.006), metastasis (p=0.024) and was significantly correlated to patients' age (p=0.009). NANOG also showed a significant positive correlation with ERα and PR receptors expression (p=0.004 and 0.005 respectively). Kaplan–Meier curves disclosed that NANOG (p=0.028, 0.050) positive expression was associated with worse DFS and OS, while OCT4 (p=0.200, 0.205) was correlated with poor DFS and OS but not significant statistically. Univariate analysis using Cox proportional hazards regression model analysis showed that OCT4 (p = 0.002), NANOG (p = 0.021), and ERα status (p = 0.004) had significant predictive values for poor DFS. However, the multivariate analysis did not show that any of them can be used as independent prognostic markers for DSF. Conclusions: From these findings, it may be concluded that the upregulated expressions of OCT4 and NANOG were associated with worse clinical outcome and could be used as predictive markers for poor DFS in BC patients.

breast cancer stemness markers Oct-4 NANOG prognosis

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Cancer. 2018; 8(6): 394-424.
[2]  Na J, Plews J, Li J, Wongtrakoongate P, Tuuri T, Feki A, et al. Molecular mechanisms of pluripotency and reprogramming. Stem Cell Res Ther. 2010; 1(4): 33.
[3]  Gangopadhyay S, Nandy A, Hor P, Mukhopadhyay A. Breast cancer stem cells: a novel therapeutic target. Clin Breast Cancer. 2013; 13(1): 7-15.
[4]  Kasai T, Chen L, Mizutani A, Kudoh T, Murakami H, Fu L, Cancer Stem Cells Converted from Pluripotent Stem Cells and the Cancerous Niche. J Stem Cells Regen Med. 2014;10(1): 2-7.
[5]  Zeineddine D, Abou Hammoud A, Mortada M, Boeuf H. The Oct4 protein: more than a magic stemness marker. Am J Stem Cells. 2014; 3(2): 74-82.
[6]  Noh KH, Kim BW, Song K-H, Cho H, Lee YH, Kim JH et al. Nanog signaling in cancer promotes stem-like phenotype and immune evasion. J Clin Invest. 2012; 122(11): 4077.
[7]  Darini C, Pisani D, Hofman P, Pedeutour F, Sudaka I, Chomienne C, et al. Self-renewal gene tracking to identify tumour-initiating cells associated with metastatic potential. Oncogene. 2012; 31(19): 2438-49.
[8]  She S, Wei Q, Kang B, Wang YJ. Cell cycle and pluripotency: Convergence on octamerbinding transcription factor 4 (Review). Mol Med Rep. 2017; 16(5): 6459-66.
[9]  Li R, Huang J, Ma M, Lou Y, Zhang Y, Wu L, et al. Two-stage induced differentiation of OCT4+/Nanog+ stem-like cells in lung adenocarcinoma. Oncotarget. 2016; 7(42): 68360-70.
[10]  Monajemzadeh M, Soleimani V, Vasei M, Koochakzadeh L, Karbakhsh M. Expression and prognostic significance of Oct4 and Nanog in neuroblastoma. APMIS. 2014; 122(9): 734-41.
[11]  You L, Guo X, Huang Y. Correlation of Cancer Stem-Cell Markers OCT4, SOX2, and NANOG with Clinicopathological Features and Prognosis in Operative Patients with Rectal Cancer. Yonsei Med J. 2018; 59(1): 35-42.
[12]  Ito T, Sato N, Yamaguchi Y, Tazawa C, Moriya T, Hirakawa H. Differences in stemness properties associated with the heterogeneity of luminal-type breast cancer. Clin Breast Cancer. 2015;15(2):e93-103. doi: 10.1016/j.clbc.2014.11.002.
[13]  Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133: 704-15
[14]  Yin X, Zhang BH, Zheng SS, Gao DM, Qiu ShJ, Wu WZ, et al. Coexpression of gene Oct4 and Nanog initiates stem cell characteristics in hepatocellular carcinoma and promotes epithelial-mesenchymal transition through activation of Stat3/Snail signaling. J Hematol Oncol. 2015; 8: 23.
[15]  Apostolou P, Toloudi M, Papasotiriou I. Identification of genes involved in breast cancer and breast cancer stem cells. Breast cancer (Dove Medical Press). 2015; 7: 183-91.
[16]  Young RA. Control of the embryonic stem cell state. Cell 2011; 144: 940-54.
[17]  Seymour T, Twigger A-J, Kakulas F. Pluripotency Genes and Their Functions in the Normal and Aberrant Breast and Brain. Int J Mol Sci. 2015; 16: 27288-301.
[18]  Wang YJ, Herlyn M. The emerging roles of Oct4 in tumor-initiating cells. Am J Physiol Cell Physiol. 2015; 309(11): C709-C18.
[19]  Madjd Z, Hashemi F, Shayanfar N, Farahani E, Zarnani AH, Sharifi AM, et al. OCT-4, an Embryonic Stem Cell Marker Expressed in Breast, Brain and Thyroid Carcinomas Compared to Testicular Carcinoma. IJCP. 2009; 2(4): 167-73.
[20]  Kumar SM, Liu S, Lu H, Zhang H, Zhang PJ, Gimotty PA, et al. Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation. Oncogene. 2012; 31(47): 4898-911.
[21]  Gwak JM, Kim M, Kim HJ, Jang MH, Park, SY. Expression of embryonal stem cell transcription factors in breast cancer: Oct4 as an indicator for poor clinical outcome and tamoxifen resistance. Oncotarget. 2017; 8(22): 36305-18.
[22]  Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003; 113: 643-55.
[23]  Lu X, Mazur SJ, Lin T, Appella E, Xu Y. The pluripotency factor nanog promotes breast cancer tumorigenesis and metastasis. Oncogene. 2014; 33(20): 2655-64.
[24]  Liao WY, Liaw CC, Huang YC, Han HY, Hsu HW, Hwang SM, et al. Cyclohexylmethyl flavonoids suppress propagation of breast cancer stem cells via downregulation of NANOG. Evid Based Complement Alternat Med. 2013; 2013: 170261.
[25]  Han J, Zhang F, Yu M, Zhao P, Ji W, Zhang H, et al. RNA interference-mediated silencing of NANOG reduces cell proliferation and induces G0/G1 cell cycle arrest in breast cancer cells. Cancer Lett. 2012; 321: 80-8.
[26]  Rasti A, Mehrazma M, Madjd Z, Abolhasani M, Saeednejad Zanjani L, Asgari M. Co-expression of Cancer Stem Cell Markers OCT4 and NANOG Predicts Poor Prognosis in Renal Cell Carcinomas. Sci Rep. 2018; 8(1): 11739.
[27]  Yu B, Cai H, Xu Z, Xu T, Zou Q, Gu M. Expressions of stem cell transcription factors Nanog and Oct4 in renal cell carcinoma tissues and clinical significance. Artif Cells Nanomed Biotechnol. 2016; 44(8): 1818-23.
[28]  Luo W, Li S, Peng B, Ye Y, DengX, Yao K. Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma. PLOS ONE. 2013; 8(2): e56324.
[29]  Yang F, Zhang J, Yang H. OCT4, SOX2, and NANOG positive expression correlates with poor differentiation, advanced disease stages, and worse overall survival in HER2+ breast cancer patients. Oncotarget. 2018; 11: 7873-81.
[30]  Liu T, Sun B, Zhao X, Li Y, Gu Q, Dong X, et al. OCT4 expression and vasculogenic mimicry formation positively correlate with poor prognosis in human breast cancer. Int J Mol Sci. 2014; 15(11): 19634-49.
[31]  Nagata T, Shimada Y, Sekine S, Moriyama M, Hashimoto I, Matsui K, et al. KLF4 and NANOG are prognostic biomarkers for triple-negative breast cancer. Breast Cancer. 2017; 24(2): 326-35.
[32]  Jin C, Zhang X, Sun M, Zhang Y, Zhang G, Wang B. Clinical implications of the coexpression of SRC1 and NANOG in HER-2-overexpressing breast cancers. Onco Targets Ther. 2016; 9: 5483-88.
[33]  Wang D, Lu P, Zhang H, Luo M, Zhang X, Wei X, et al. Oct-4 and Nanog promote the epithelial-mesenchymal transition of breast cancer stem cells and are associated with poor prognosis in breast cancer patients. Oncotarget. 2014; 5(21), 10803-15.
[34]  Phillips TM, McBride WH, Pajonk F. The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006; 98: 1777-85.
[35]  Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100: 672-9.
[36]  Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 2010; 70(24): 10433-44.
[37]  Krogh Petersen J, Jensen P, Dahl Sørensen M, Winther Kristensen B. Expression and Prognostic Value of Oct-4 in Astrocytic Brain Tumors. PLOS ONE. 2016; 11(12): e0169129.
[38]  Chang T-S, Wu Y-C, Chi C-C, Su W-C, Chang P-J, Lee K-F. Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression. Clin Cancer Res. 2014; 21(1); 201-10.
[39]  Yin X, Li YW, Zhang BH, Ren ZG, Qiu SJ, Yi Y, Fan J. Coexpression of stemness factors Oct4 and Nanog predict liver resection. Ann Surg Oncol. 2012; 19(9): 2877-87.