OCT4 but not SOX2 expression correlates with worse prognosis in surgical patients with triple-negative breast cancer

Original Article



Octamer-binding transcription factor 4 (OCT4) and SRY (sex determining region Y)-box 2 (SOX2) are common biomarkers of cancer stem cells, which contribute to the pathological processes of several carcinomas, while little is known about the effects of OCT4 and SOX2 on the prognosis of triple-negative breast cancer (TNBC). The purpose was to evaluate the correlation of tumor tissue OCT4 and SOX2 expressions with clinicopathological features and overall survival (OS) in surgical TNBC patients.


127 surgical patients with TNBC were enrolled in this cohort study. Tumor tissue samples were obtained during the operation. OCT4 and SOX2 expressions were assessed by immunofluorescent staining.


32 (25%) TNBC patients with OCT4 positive expression (OCT4+), 21 (17%) patients with SOX2 positive expression (SOX2+), and 11 (9%) patients with both OCT4+ and SOX2+ were observed. OCT4 expression was positively associated with histologic grade (P < 0.001), pathological tumor size (P = 0.014), N stage (P < 0.001) and TNM stage (P < 0.001), while SOX2 expression was positively correlated with histologic grade (P < 0.001), pathological tumor size (P = 0.033) and Ki-67 expression (P = 0.016). Kaplan–Meier (K–M) curves suggested OCT4+ was correlated with shorter OS compared with OCT4 (P < 0.001), while no correlation between SOX2+ with OS in all patients (P = 0.128) was observed. Multivariate Cox model indicated that OCT4+ (P < 0.001) were independent factors for worse OS.


Tumor tissue OCT4 but not SOX2 expression was positively correlated with histologic grade, pathological tumor size, N stage and TNM stage, and it could be served as an independent biomarker to predict worse prognosis in surgical patients with TNBC.


Tumor tissue OCT4 SOX2 Prognosis Triple-negative breast cancer 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12282_2018_844_MOESM1_ESM.pdf (12 kb)
Supplementary material 1 (PDF 11 kb)


  1. 1.
    Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389(10074):1134–50.  https://doi.org/10.1016/S0140-6736(16)31891-8.CrossRefPubMedGoogle Scholar
  2. 2.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.  https://doi.org/10.3322/caac.21262.CrossRefPubMedGoogle Scholar
  3. 3.
    Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938–48.  https://doi.org/10.1056/NEJMra1001389.CrossRefPubMedGoogle Scholar
  4. 4.
    Brewster AM, Chavez-MacGregor M, Brown P. Epidemiology, biology, and treatment of triple-negative breast cancer in women of African ancestry. Lancet Oncol. 2014;15(13):e625–34.  https://doi.org/10.1016/S1470-2045(14)70364-X.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.  https://doi.org/10.1172/JCI45014.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer. 2013;13(10):727–38.  https://doi.org/10.1038/nrc3597.CrossRefPubMedGoogle Scholar
  7. 7.
    Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12(11):767–75.  https://doi.org/10.1038/nrc3368.CrossRefPubMedGoogle Scholar
  8. 8.
    Yu L, Jiao YJ, Zhou L, Song WQ, Wu SW, Wang DN. Expressions of OCT4, Notch1 and DLL4 and their clinical implications in epithelial ovarian cancer. Nan Fang Yi Ke Da Xue Xue Bao. 2016;37(4):444–50.PubMedGoogle Scholar
  9. 9.
    Stewart CJ, Crook ML. Podoplanin and SOX2 expression in CIN 3-like squamous cell carcinoma of the cervix. Int J Gynecol Pathol. 2017.  https://doi.org/10.1097/PGP.0000000000000383.Google Scholar
  10. 10.
    Zhong F, Cheng X, Sun S, Zhou J. Transcriptional activation of PD-L1 by SOX2 contributes to the proliferation of hepatocellular carcinoma cells. Oncol Rep. 2017;37(5):3061–7.  https://doi.org/10.3892/or.2017.5523.CrossRefPubMedGoogle Scholar
  11. 11.
    Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46(10):5419–25.PubMedGoogle Scholar
  13. 13.
    Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W, et al. Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab. 1994;79(2):643–9.  https://doi.org/10.1210/jcem.79.2.7519194.PubMedGoogle Scholar
  14. 14.
    Elnemr GM, El-Rashidy AH, Osman AH, Issa LF, Abbas OA, Al-Zahrani AS, et al. Response of triple negative breast cancer to neoadjuvant chemotherapy: correlation between Ki-67 expression and pathological response. Asian Pac J Cancer Prev. 2016;17(2):807–13.CrossRefPubMedGoogle Scholar
  15. 15.
    Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. 2010;28(10):1684–91.  https://doi.org/10.1200/JCO.2009.24.9284.CrossRefPubMedGoogle Scholar
  16. 16.
    Tischkowitz M, Brunet JS, Begin LR, Huntsman DG, Cheang MC, Akslen LA, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer. 2007;7:134.  https://doi.org/10.1186/1471-2407-7-134.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368–76.  https://doi.org/10.1158/1078-0432.CCR-07-1658.CrossRefPubMedGoogle Scholar
  18. 18.
    Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 2009;18(7):1093–108.  https://doi.org/10.1089/scd.2009.0113.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cheng J, Li W, Kang B, Zhou Y, Song J, Dan S, et al. Tryptophan derivatives regulate the transcription of OCT4 in stem-like cancer cells. Nat Commun. 2015;6:7209.  https://doi.org/10.1038/ncomms8209.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hu J, Qin K, Zhang Y, Gong J, Li N, Lv D, et al. Downregulation of transcription factor OCT4 induces an epithelial-to-mesenchymal transition via enhancement of Ca2+ binflux in breast cancer cells. Biochem Biophys Res Commun. 2011;411(4):786–91.  https://doi.org/10.1016/j.bbrc.2011.07.025.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim RJ, Nam JS. OCT4 expression enhances features of cancer stem cells in a mouse model of breast cancer. Lab Anim Res. 2011;27(2):147–52.  https://doi.org/10.5625/lar.2011.27.2.147.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang YD, Cai N, Wu XL, Cao HZ, Xie LL, Zheng PS. OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway. Cell Death Dis. 2013;4:e760.  https://doi.org/10.1038/cddis.2013.272.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jen J, Tang YA, Lu YH, Lin CC, Lai WW, Wang YC. OCT4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression. Mol Cancer. 2017;16(1):104.  https://doi.org/10.1186/s12943-017-0674-z.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hatefi N, Nouraee N, Parvin M, Ziaee SA, Mowla SJ. Evaluating the expression of Oct4 as a prognostic tumor marker in bladder cancer. Iran J Basic Med Sci. 2012;15(6):1154–61.PubMedPubMedCentralGoogle Scholar
  25. 25.
    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.  https://doi.org/10.18632/oncotarget.16750.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Linn DE, Yang X, Sun F, Xie Y, Chen H, Jiang R, et al. A role for OCT4 in tumor initiation of drug-resistant prostate cancer cells. Genes Cancer. 2010;1(9):908–16.  https://doi.org/10.1177/1947601910388271.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Li B, Yao Z, Wan Y, Lin D. Overexpression of OCT4 is associated with gefitinib resistance in non-small cell lung cancer. Oncotarget. 2016;7(47):77342–7.  https://doi.org/10.18632/oncotarget.12999.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Sullivan JP, Minna JD, Shay JW. Evidence for self-renewing lung cancer stem cells and their implications in tumor initiation, progression, and targeted therapy. Cancer Metastasis Rev. 2010;29(1):61–72.  https://doi.org/10.1007/s10555-010-9216-5.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9.  https://doi.org/10.1038/nature10933.PubMedGoogle Scholar
  30. 30.
    Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.  https://doi.org/10.1038/nature10983.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Ball SG, Shuttleworth A, Kielty CM. Inhibition of platelet-derived growth factor receptor signaling regulates OCT4 and Nanog expression, cell shape, and mesenchymal stem cell potency. Stem Cells. 2012;30(3):548–60.  https://doi.org/10.1002/stem.1015.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and OCT4 via Wnt/beta-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett. 2016;374(2):292–303.  https://doi.org/10.1016/j.canlet.2016.02.032.CrossRefPubMedGoogle Scholar
  33. 33.
    Li W, Zhou Y, Zhang X, Yang Y, Dan S, Su T, et al. Dual inhibiting OCT4 and AKT potently suppresses the propagation of human cancer cells. Sci Rep. 2017;7:46246.  https://doi.org/10.1038/srep46246.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wuebben EL, Rizzino A. The dark side of SOX2: cancer—a comprehensive overview. Oncotarget. 2017;8(27):44917–43.  https://doi.org/10.18632/oncotarget.16570.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Liu K, Xie F, Gao A, Zhang R, Zhang L, Xiao Z, et al. SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis. Mol Cancer. 2017;16(1):62.  https://doi.org/10.1186/s12943-017-0632-9.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Schaefer T, Wang H, Mir P, Konantz M, Pereboom TC, Paczulla AM, et al. Molecular and functional interactions between AKT and SOX2 in breast carcinoma. Oncotarget. 2015;6(41):43540–56.  https://doi.org/10.18632/oncotarget.6183.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Singh SK, Chen NM, Hessmann E, Siveke J, Lahmann M, Singh G, et al. Antithetical NFATc1-SOX2 and p53-miR200 signaling networks govern pancreatic cancer cell plasticity. EMBO J. 2015;34(4):517–30.  https://doi.org/10.15252/embj.201489574.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hui K, Gao Y, Huang J, Xu S, Wang B, Zeng J, et al. RASAL2, a RAS GTPase-activating protein, inhibits stemness and epithelial–mesenchymal transition via MAPK/SOX2 pathway in bladder cancer. Cell Death Dis. 2017;8(2):e2600.  https://doi.org/10.1038/cddis.2017.9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Wang S, Tie J, Wang R, Hu F, Gao L, Wang W, et al. SOX2, a predictor of survival in gastric cancer, inhibits cell proliferation and metastasis by regulating PTEN. Cancer Lett. 2015;358(2):210–9.  https://doi.org/10.1016/j.canlet.2014.12.045.CrossRefPubMedGoogle Scholar
  40. 40.
    Yamawaki K, Ishiguro T, Mori Y, Yoshihara K, Suda K, Tamura R, et al. SOX2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. Cancer Sci. 2017;108(4):632–40.  https://doi.org/10.1111/cas.13196.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shen L, Huang X, Xie X, Su J, Yuan J, Chen X. High expression of SOX2 and OCT4 indicates radiation resistance and an independent negative prognosis in cervical squamous cell carcinoma. J Histochem Cytochem. 2014;62(7):499–509.  https://doi.org/10.1369/0022155414532654.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Tang XB, Shen XH, Li L, Zhang YF, Chen GQ. SOX2 overexpression correlates with poor prognosis in laryngeal squamous cell carcinoma. Auris Nasus Larynx. 2013;40(5):481–6.  https://doi.org/10.1016/j.anl.2013.01.003.CrossRefPubMedGoogle Scholar
  43. 43.
    Otsubo T, Akiyama Y, Yanagihara K, Yuasa Y. SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Br J Cancer. 2008;98(4):824–31.  https://doi.org/10.1038/sj.bjc.6604193.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chen Y, Huang Y, Zhu L, Chen M, Huang Y, Zhang J, et al. SOX2 inhibits metastasis in gastric cancer. J Cancer Res Clin Oncol. 2016;142(6):1221–30.  https://doi.org/10.1007/s00432-016-2125-4.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2018

Authors and Affiliations

  1. 1.Department of Thyroid Breast Surgery, The Central Hospital of Wuhan, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations