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image of SOX9 Promotes Breast Cancer Progression via the EGFR/STAT3 Signaling Axis

Abstract

Introduction

Sex-determining region Y-box 9 (SOX9) is a transcription factor frequently overexpressed in breast cancer, playing a critical role in tumor initiation, progression, and therapeutic resistance. While its oncogenic potential is recognized, the underlying molecular mechanisms remain incompletely elucidated. This study aimed to investigate the functional role of SOX9 in breast cancer, specifically focusing on its interaction with the EGFR/STAT3 signaling pathway.

Methods

The study integrated bioinformatics analyses with functional assays in breast cancer cell lines to determine the effects of SOX9 modulation on cell proliferation, migration, and invasion, and to elucidate its connection with the EGFR/STAT3 signaling axis.

Results

Our findings demonstrate that SOX9 promotes breast cancer cell proliferation, migration, and invasion. Mechanistically, this occurs through the activation of the EGFR/STAT3 signaling axis. Furthermore, targeting SOX9 effectively attenuated these oncogenic phenotypes .

Discussion

The elucidation of SOX9’s role in activating the EGFR/STAT3 pathway significantly advances our understanding of its oncogenic mechanisms in breast cancer. These findings are consistent with existing literature on SOX9’s pro-tumorigenic impact and the established role of EGFR/STAT3 signaling in cancer progression, highlighting a crucial regulatory link. This newly identified SOX9-EGFR/STAT3 axis not only reinforces SOX9’s prognostic value but also strongly supports its exploration as a novel therapeutic target.

Conclusion

These findings identify SOX9 as a key regulator of the EGFR/STAT3 signaling pathway in breast cancer. This highlights the potential of SOX9 as both a prognostic biomarker and a promising target for drug therapy in breast cancer.

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2025-08-22
2025-12-17
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References

  1. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021 71 3 209 249 10.3322/caac.21660 33538338
    [Google Scholar]
  2. Harbeck N. Penault-Llorca F. Cortes J. Gnant M. Houssami N. Poortmans P. Ruddy K. Tsang J. Cardoso F. Breast cancer. Nat. Rev. Dis. Primers 2019 5 1 66 10.1038/s41572‑019‑0111‑2 31548545
    [Google Scholar]
  3. Jo A. Denduluri S. Zhang B. Wang Z. Yin L. Yan Z. Kang R. Shi L.L. Mok J. Lee M.J. Haydon R.C. The versatile functions of Sox9 in development, stem cells, and human diseases. Genes Dis. 2014 1 2 149 161 10.1016/j.gendis.2014.09.004 25685828
    [Google Scholar]
  4. Guo W. Keckesova Z. Donaher J.L. Shibue T. Tischler V. Reinhardt F. Itzkovitz S. Noske A. Zürrer-Härdi U. Bell G. Tam W.L. Mani S.A. van Oudenaarden A. Weinberg R.A. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012 148 5 1015 1028 10.1016/j.cell.2012.02.008 22385965
    [Google Scholar]
  5. Domenici G. Aurrekoetxea-Rodríguez I. Simões B.M. Rábano M. Lee S.Y. Millán J.S. Comaills V. Oliemuller E. López-Ruiz J.A. Zabalza I. Howard B.A. Kypta R.M. Vivanco M.A. Sox2–Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells. Oncogene 2019 38 17 3151 3169 10.1038/s41388‑018‑0656‑7 30622340
    [Google Scholar]
  6. Ma F. Ye H. He H.H. Gerrin S.J. Chen S. Tanenbaum B.A. Cai C. Sowalsky A.G. He L. Wang H. Balk S.P. Yuan X. SOX9 drives WNT pathway activation in prostate cancer. J. Clin. Invest. 2016 126 5 1745 1758 10.1172/JCI78815 27043282
    [Google Scholar]
  7. Yu H. Lee H. Herrmann A. Buettner R. Jove R. Revisiting STAT3 signalling in cancer: New and unexpected biological functions. Nat. Rev. Cancer 2014 14 11 736 746 10.1038/nrc3818 25342631
    [Google Scholar]
  8. Kolarova I. Melichar B. Vanasek J. Controversies of radiotherapy in human epidermal growth factor receptor (HER)-2 positive breast cancer patients. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2021 165 1 19 25 10.5507/bp.2021.007 33542544
    [Google Scholar]
  9. Johnson D.E. O’Keefe R.A. Grandis J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 2018 15 4 234 248 10.1038/nrclinonc.2018.8 29405201
    [Google Scholar]
  10. Qin J.J. Yan L. Zhang J. Zhang W.D. STAT3 as a potential therapeutic target in triple negative breast cancer: A systematic review. J. Exp. Clin. Cancer Res. 2019 38 1 195 10.1186/s13046‑019‑1206‑z 31088482
    [Google Scholar]
  11. Santos J.C. Carrasco-Garcia E. Garcia-Puga M. Aldaz P. Montes M. Fernandez-Reyes M. de Oliveira C.C. Lawrie C.H. Araúzo-Bravo M.J. Ribeiro M.L. Matheu A. SOX9 elevation acts with canonical WNT signaling to drive gastric cancer progression. Cancer Res. 2016 76 22 6735 6746 10.1158/0008‑5472.CAN‑16‑1120 27569216
    [Google Scholar]
  12. Sun Y. Zhang C. Fang Q. Zhang W. Liu W. Abnormal signal pathways and tumor heterogeneity in osteosarcoma. J. Transl. Med. 2023 21 1 99 10.1186/s12967‑023‑03961‑7 36759884
    [Google Scholar]
  13. Ma Y. Shepherd J. Zhao D. Bollu L.R. Tahaney W.M. Hill J. Zhang Y. Mazumdar A. Brown P.H. SOX9 is essential for triple-negative breast cancer cell survival and metastasis. Mol. Cancer Res. 2020 18 12 1825 1838 10.1158/1541‑7786.MCR‑19‑0311 32661114
    [Google Scholar]
  14. Xu Y.R. Yang W.X. SOX-mediated molecular crosstalk during the progression of tumorigenesis. Semin. Cell Dev. Biol. 2017 63 23 34 10.1016/j.semcdb.2016.07.028 27476113
    [Google Scholar]
  15. Jana S. Madhu Krishna B. Singhal J. Horne D. Awasthi S. Salgia R. Singhal S.S. SOX9: The master regulator of cell fate in breast cancer. Biochem. Pharmacol. 2020 174 113789 10.1016/j.bcp.2019.113789 31911091
    [Google Scholar]
  16. Wan Y.P. Xi M. He H.C. Wan S. Hua W. Zen Z.C. Liu Y.L. Zhou Y.L. Mo R.J. Zhuo Y.J. Luo H.W. Jiang F.N. Zhong W.D. Expression and clinical significance of SOX9 in renal cell carcinoma, bladder cancer and penile cancer. Oncol. Res. Treat. 2017 40 1-2 15 20 10.1159/000455145 28118628
    [Google Scholar]
  17. Tang L. Jin J. Xu K. Wang X. Tang J. Guan X. SOX9 interacts with FOXC1 to activate MYC and regulate CDK7 inhibitor sensitivity in triple-negative breast cancer. Oncogenesis 2020 9 5 47 10.1038/s41389‑020‑0232‑1 32398735
    [Google Scholar]
  18. Wang Y.F. Dang H.F. Luo X. Wang Q.Q. Gao C. Tian Y.X. Downregulation of SOX9 suppresses breast cancer cell proliferation and migration by regulating apoptosis and cell cycle arrest. Oncol. Lett. 2021 22 1 517 10.3892/ol.2021.12778 33986877
    [Google Scholar]
  19. Tang T. Guo C. Xia T. Zhang R. Zen K. Pan Y. Jin L. LncCCAT1 promotes breast cancer stem cell function through activating WNT/β-catenin signaling. Theranostics 2019 9 24 7384 7402 10.7150/thno.37892 31695775
    [Google Scholar]
  20. Morillo-Bernal J. Pizarro-García P. Moreno-Bueno G. Cano A. Mazón M.J. Eraso P. Portillo F. HuR (ELAVL1) stabilizes SOX9 mRNA and promotes migration and invasion in breast cancer cells. Cancers 2024 16 2 384 10.3390/cancers16020384 38254873
    [Google Scholar]
  21. Wang H. Yao F. Luo S. Ma K. Liu M. Bai L. Chen S. Song C. Wang T. Du Q. Wu H. Wei M. Fang Y. Xiao Q. A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis. Cancer Lett. 2019 455 48 59 10.1016/j.canlet.2019.04.027 31042586
    [Google Scholar]
  22. Aguilar-Medina M. Avendaño-Félix M. Lizárraga-Verdugo E. Bermúdez M. Romero-Quintana J.G. Ramos-Payan R. Ruíz-García E. López-Camarillo C. Sox9 stem-cell factor: Clinical and functional relevance in cancer. J. Oncol. 2019 2019 1 16 10.1155/2019/6754040 31057614
    [Google Scholar]
  23. Song X. Liu Z. Yu Z. EGFR promotes the development of triple negative breast cancer through JAK/STAT3 signaling. Cancer Manag. Res. 2020 12 703 717 10.2147/CMAR.S225376 32099467
    [Google Scholar]
  24. Zhao Y. Pang W. Yang N. Hao L. Wang L. MicroRNA-511 inhibits malignant behaviors of breast cancer by directly targeting SOX9 and regulating the PI3K/Akt pathway. Int. J. Oncol. 2018 53 6 2715 2726 10.3892/ijo.2018.4576 30272349
    [Google Scholar]
  25. Gao J.B. Zhu M.N. Zhu X.L. miRNA‐215‐5p suppresses the aggressiveness of breast cancer cells by targeting Sox9. FEBS Open Bio 2019 9 11 1957 1967 10.1002/2211‑5463.12733 31538724
    [Google Scholar]
  26. Chun J. Song K. Kim Y.S. Sesquiterpene lactones‐enriched fraction of Inula helenium L. induces apoptosis through inhibition of signal transducers and activators of transcription 3 signaling pathway in MDA‐MB‐231 breast cancer cells. Phytother. Res. 2018 32 12 2501 2509 10.1002/ptr.6189 30251272
    [Google Scholar]
  27. Riemenschnitter C. Teleki I. Tischler V. Guo W. Varga Z. Stability and prognostic value of Slug, Sox9 and Sox10 expression in breast cancers treated with neoadjuvant chemotherapy. Springerplus 2013 2 1 695 10.1186/2193‑1801‑2‑695 24404438
    [Google Scholar]
  28. Jeselsohn R. Cornwell M. Pun M. Buchwalter G. Nguyen M. Bango C. Huang Y. Kuang Y. Paweletz C. Fu X. Nardone A. De Angelis C. Detre S. Dodson A. Mohammed H. Carroll J.S. Bowden M. Rao P. Long H.W. Li F. Dowsett M. Schiff R. Brown M. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance. Proc. Natl. Acad. Sci. USA 2017 114 22 E4482 E4491 10.1073/pnas.1620993114 28507152
    [Google Scholar]
  29. Fazilaty H. Gardaneh M. Akbari P. Zekri A. Behnam B. SLUG and SOX9 cooperatively regulate tumor initiating niche factors in breast cancer. Cancer Microenviron. 2016 9 1 71 74 10.1007/s12307‑015‑0176‑8 26412079
    [Google Scholar]
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