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Tumor Biology

, Volume 36, Issue 6, pp 4167–4173 | Cite as

SOX4 overexpression is a novel biomarker of malignant status and poor prognosis in breast cancer patients

  • Guo-Dong Song
  • Yu Sun
  • Hong Shen
  • Wei Li
Research Article

Abstract

Sex-determining region Y-related high mobility group box 4 (SOX4) has been proven to serve as a critical role in cancer development and progression. However, little is known about the pathological role of SOX4 in breast cancer patients. The purpose of this study is to measure the expression of SOX4 in breast cancer patients and to explore the clinical significance of SOX4. Using RT-PCR and Western blot, messenger RNA (mRNA) and protein expression of SOX4 were measured in breast cancer tissues and adjacent normal mammary tissues. The relationship of SOX4 expression with clinical characteristics of 148 breast cancer patients was analyzed by immunohistochemistry. In the present study, our results indicated that SOX4 mRNA and protein were highly expressed in breast cancer tissues compared with adjacent normal mammary tissues and positively correlated with clinical stage (I–II vs. III–IV; P = 0.008), T classification (T1–T2 vs. T3–T4; P = 0.013), N classification (N0–N1 vs. N2–N3; P < 0.001), M classification (M0 vs. M1; P = 0.001), estrogen receptor (negative vs. positive; P = 0.029), progesterone receptor (negative vs. positive; P = 0.004), and histological grade (G1 vs. G2–G3; P = 0.033) in breast cancer patients. Furthermore, we also found that SOX4 protein overexpression was an unfavorable prognostic factor in breast cancer patients (P < 0.001), regardless of clinical stage, tumor size, lymph node metastasis, and distant metastasis. Finally, high SOX4 expression was an independent poor prognostic factor for pancreatic patients through multivariate analysis (P = 0.033). In conclusion, SOX4 overexpression serves as an unfavorable prognostic biomarker in breast cancer patients.

Keywords

SOX4 Breast cancer Prognosis Biomarker 

Notes

Conflicts of interest

None

References

  1. 1.
    Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol. 2011;223:307–17.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA: A Cancer J Clin. 2014;64:9–29.Google Scholar
  3. 3.
    Hong W, Dong E. The past, present and future of breast cancer research in China. Cancer Lett. 2014;351:1–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951–3.CrossRefPubMedGoogle Scholar
  5. 5.
    Radenkovic S, Milosevic Z, Konjevic G, Karadzic K, Rovcanin B, Buta M, et al. Lactate dehydrogenase, catalase, and superoxide dismutase in tumor tissue of breast cancer patients in respect to mammographic findings. Cell Biochem Biophys. 2013;66:287–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Radenkovic S, Konjevic G, Jurisic V, Karadzic K, Nikitovic M, Gopcevic K. Values of mmp-2 and mmp-9 in tumor tissue of basal-like breast cancer patients. Cell Biochem Biophys. 2014;68:143–52.CrossRefPubMedGoogle Scholar
  7. 7.
    Radenkovic S, Konjevic G, Isakovic A, Stevanovic P, Gopcevic K, Jurisic V. Her2-positive breast cancer patients: correlation between mammographic and pathological findings. Radiat Prot Dosim. 2014;162:125–8.CrossRefGoogle Scholar
  8. 8.
    Jafarnejad SM, Ardekani GS, Ghaffari M, Li G. Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis. Cell Mol Life Sci: CMLS. 2013;70:2677–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Vervoort SJ, van Boxtel R, Coffer PJ. The role of SRY-related HMG box transcription factor 4 (SOX4) in tumorigenesis and metastasis: friend or foe? Oncogene. 2013;32:3397–409.CrossRefPubMedGoogle Scholar
  10. 10.
    Peluso S, Chiappetta G. High-mobility group A (HMGA) proteins and breast cancer. Breast Care (Basel, Switzerland). 2010;5:81–5.CrossRefGoogle Scholar
  11. 11.
    Zhang J, Liang Q, Lei Y, Yao M, Li L, Gao X, et al. SOX4 induces epithelial-mesenchymal transition and contributes to breast cancer progression. Cancer Res. 2012;72:4597–608.CrossRefPubMedGoogle Scholar
  12. 12.
    Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol. 2007;27:7802–15.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Andersen CL, Christensen LL, Thorsen K, Schepeler T, Sorensen FB, Verspaget HW, et al. Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer. Br J Cancer. 2009;100:511–23.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Liao YL, Sun YM, Chau GY, Chau YP, Lai TC, Wang JL, et al. Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene. 2008;27:5578–89.CrossRefPubMedGoogle Scholar
  15. 15.
    Hur W, Rhim H, Jung CK, Kim JD, Bae SH, Jang JW, et al. SOX4 overexpression regulates the p53-mediated apoptosis in hepatocellular carcinoma: clinical implication and functional analysis in vitro. Carcinogenesis. 2010;31:1298–307.CrossRefPubMedGoogle Scholar
  16. 16.
    Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB, et al. Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res. 2006;66:4011–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Moreno CS. The sex-determining region Y-box 4 and homeobox c6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. Am J Pathol. 2010;176:518–27.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shen R, Pan S, Qi S, Lin X, Cheng S. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem Biophys Res Commun. 2010;394:1047–52.CrossRefPubMedGoogle Scholar
  19. 19.
    Fang CL, Hseu YC, Lin YF, Hung ST, Tai C, Uen YH, et al. Clinical and prognostic association of transcription factor SOX4 in gastric cancer. PLoS One. 2012;7:e52804.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Huang HY, Cheng YY, Liao WC, Tien YW, Yang CH, Hsu SM, et al. SOX4 transcriptionally regulates multiple sema3/plexin family members and promotes tumor growth in pancreatic cancer. PLoS One. 2012;7:e48637.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang H, Alberich-Jorda M, Amabile G, Yang H, Staber PB, Di Ruscio A, et al. SOX4 is a key oncogenic target in C/EBPalpha mutant acute myeloid leukemia. Cancer Cell. 2013;24:575–88.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang L, Li Y, Yang X, Yuan H, Li X, Qi M, et al. ERG-SOX4 interaction promotes epithelial-mesenchymal transition in prostate cancer cells. Prostate. 2014;74:647–58.CrossRefPubMedGoogle Scholar
  23. 23.
    Jafarnejad SM, Ardekani GS, Ghaffari M, Martinka M, Li G. SOX4-mediated dicer expression is critical for suppression of melanoma cell invasion. Oncogene. 2013;32:2131–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang L, Zhang J, Yang X, Chang YW, Qi M, Zhou Z, et al. SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro. Prostate Cancer Prostatic Dis. 2013;16:301–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Vervoort SJ, Lourenco AR, van Boxtel R, Coffer PJ. SOX4 mediates TGF-beta-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition. PLoS One. 2013;8:e53238.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P, Pachkov M, et al. SOX4 is a master regulator of epithelial-mesenchymal transition by controlling EZH2 expression and epigenetic reprogramming. Cancer Cell. 2013;23:768–83.CrossRefPubMedGoogle Scholar
  27. 27.
    Jafarnejad SM, Wani AA, Martinka M, Li G. Prognostic significance of SOX4 expression in human cutaneous melanoma and its role in cell migration and invasion. Am J Pathol. 2010;177:2741–52.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang C, Zhao H, Lu J, Yin J, Zang L, Song N, et al. Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma. Diagn Pathol. 2012;7:41.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ramezani-Rad P, Geng H, Hurtz C, Chan LN, Chen Z, Jumaa H, et al. SOX4 enables oncogenic survival signals in acute lymphoblastic leukemia. Blood. 2013;121:148–55.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of SurgeryThe Second Hospital of Tianjin Medical UniversityTianjinChina

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