Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
2014-February Volume 44 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
2014-February Volume 44 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits

Corrigendum in: /10.3892/ijo.2025.5775
  • Authors:
    • Seyung S. Chung
    • Nolan Giehl
    • Yanyuan Wu
    • Jaydutt V. Vadgama
  • View Affiliations / Copyright

    Affiliations: Division of Cancer Research and Training, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
    Copyright: © Chung et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 403-411
    |
    Published online on: November 29, 2013
       https://doi.org/10.3892/ijo.2013.2195
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Clinically, HER2 proto-oncogene amplification is found in about 25-30% of human breast cancers, where it is correlated to a poor prognosis. Constitutive STAT3 activation is found in about 50-60% of the breast tumors and associated with tumorigenesis and drug resistance. In this study, we showed that STAT3 was phosphorylated in HER2-overexpressing, ER-positive human breast tumors and, furthermore, phosphorylated STAT3 promoted the stem-like cell phenotype. We examined the dysregulation of the stem cell markers (Oct-4, Sox-2 and CD44) and the tumorsphere formation in HER2-overexpressing human breast cancer cell lines. We demonstrated that the STAT3 inhibitor, Stattic, treatment abolished the cancer stem cell phenotype in HER2-positive breast cancers. Combined treatment of Herceptin and Stattic showed the synergistic effect on the cancer cell growth in vitro. In addition, when the STAT3 gene was knocked down, the expression of the stem cell markers Oct-4, Sox-2 and CD44 were downregulated and tumorsphere formation was abolished. HER2-elicited STAT3 signaling may provide a potential model for drug resistance induced by stem-like cell characteristics. This mechanism may be responsible for acquiring resistance to Herceptin in the treatment of HER2-overexpressing breast tumors. Based on our findings, targeting pSTAT3 could overcome Herceptin-induced resistance in HER2-overexpressing breast tumors.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1. 

Wu Y, Elshimali Y, Sarkissyan M, Mohamed H, Clayton S and Vadgama JV: Expression of FOXO1 is associated with GATA3 and Annexin-1 and predicts disease-free survival in breast cancer. Am J Cancer Res. 2:104–115. 2012.PubMed/NCBI

2. 

Hartman Z, Yang X, Glass O, Lei G, Osada T, Dave SS, et al: HER2 overexpression elicits proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 71:4380–4391. 2011. View Article : Google Scholar : PubMed/NCBI

3. 

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ulrich A and McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER2/neu oncogene. Science. 235:177–182. 1987. View Article : Google Scholar : PubMed/NCBI

4. 

Hynes NE and Stern DF: The biology of erbB-2/neu/HER2 and its role in cancer. Biochim Biophys Acta. 1198:165–184. 1994.PubMed/NCBI

5. 

Yarden Y: Biology of HER2 and its importance in breast cancer. Oncology. 61:1–13. 2001. View Article : Google Scholar : PubMed/NCBI

6. 

Pegram MD, Konecny G and Slamon DJ: The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of Herceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res. 103:57–75. 2000. View Article : Google Scholar : PubMed/NCBI

7. 

Zhang W, Ding W, Chen Y, Feng M, Ouyang Y, Yu Y and He Z: Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF-7 breast cancer cells. Acta Biochim Biophys Sin (Shanghai). 43:647–653. 2011. View Article : Google Scholar

8. 

Siddiqa A, Long L, Li L, Marciniak R and Kazhdan I: Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signaling pathways. BMC Cancer. 8:1292008. View Article : Google Scholar

9. 

Gemmete JJ and Mukherji SK: Trastuzumab (herceptin). Am J Neuroradiol. 32:1373–1374. 2011. View Article : Google Scholar : PubMed/NCBI

10. 

Harbeck N, Pegram MD, Rüschoff J and Möbus V: Targeted therapy in metastatic breast cancer: the HER2/neu oncogene. Breast Care (Basel). 5(Suppl 1): 3–7. 2010. View Article : Google Scholar : PubMed/NCBI

11. 

Hubalek M, Brunner C, Matthä K and Marth C: Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. Wien Med Wochenschr. 160:506–512. 2010. View Article : Google Scholar : PubMed/NCBI

12. 

Cheng GZ, Zhang W, Sun M, Wang Q, Coppola D, Mansour M, et al: Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem. 283:14665–14673. 2008. View Article : Google Scholar : PubMed/NCBI

13. 

Lin L, Hutzen B, Zuo M, Ball S, Deangelis S and Foust E: Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. 70:2445–2454. 2010. View Article : Google Scholar : PubMed/NCBI

14. 

Armanious H, Gelebart P, Mackey J, Ma Y and Lai R: STAT3 upregulates the protein expression and transcriptional activity of β-catenin in breast cancer. Int J Clin Exp Pathol. 3:654–664. 2010.

15. 

Zhong Z, Wen Z and Darnell J: Stat3: a STAT3 family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264:95–98. 1994. View Article : Google Scholar : PubMed/NCBI

16. 

Hart JR, Liao L, Yates J and Vogt P: Essential role of Stat3 in PI3K-induced oncogenic transformation. Proc Natl Acad Sci USA. 108:13247–13252. 2011. View Article : Google Scholar : PubMed/NCBI

17. 

Yang Z, Cai J, Xie S, Li G, Song W, Yan Q, Yan L and Zhang F: Therapeutic effects of signal transducer and activator of transcription 3 siRNA on human breast cancer in xenograft mice. Chin Med J. 124:1854–1861. 2011.PubMed/NCBI

18. 

Yi EH, Lee CS, Lee JK, Lee YJ, Shin MK, Cho CH, et al: STAT3-RANTES autocrine signaling is essential for tamoxifen rsistance in human breast cancer cells. Mol Cancer Res. 11:31–42. 2013. View Article : Google Scholar : PubMed/NCBI

19. 

Marotta LC, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al: The JAK2/STAT3 signaling pathway is required for growth of CD44+CD24− stem cell-like breast cancer cells in human tumors. J Clin Invest. 121:2723–2735. 2011. View Article : Google Scholar : PubMed/NCBI

20. 

Oliveras-Ferraros C, Vazquez-Martin A, Martin-Castillo B, Cufi S, Del Barco S, Lopez-Bonet E, et al: Dynamic emergence of the mesenchymal CD44pos/CD24neg/low phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin). Biochem Biophys Res Commun. 397:27–33. 2010. View Article : Google Scholar : PubMed/NCBI

21. 

Fang X, Cai Y, Liu J, Wang Z, Wu Q, Zhang Z, et al: Twist2 contributes to breast cancer progression by promoting an epithelial-mesenchymal transition and cancer stem-like self-renewal. Oncogene. 30:4707–4720. 2011. View Article : Google Scholar : PubMed/NCBI

22. 

Berishaj M, Gao SP, Ahmed S, Leslie K, Al-Ahmadie H, Gerald W, et al: Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res. 9:R322007. View Article : Google Scholar : PubMed/NCBI

23. 

Schust J, Sperl B, Hollis A, Mayer T and Berg T: Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 13:1235–1242. 2006. View Article : Google Scholar : PubMed/NCBI

24. 

Kong D, Li Y, Wang Z and Sarkar FH: Cancer stem cells and epithelial-to-mesenchymal transition (EMT)-phenotypic cells: are they cousins or twins? Cancers (Basel). 3:716–729. 2011. View Article : Google Scholar : PubMed/NCBI

25. 

Sato T, Neilson LM, Peck AR, Liu C, Tran T, Witkiewicz A, et al: Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res. 1:347–355. 2011.PubMed/NCBI

26. 

Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Panday MK, Kunnunmakkara AB, et al: Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann NY Acad Sci. 1091:151–169. 2006. View Article : Google Scholar : PubMed/NCBI

27. 

Masuda M, Wakasaki T, Suzui M, Toh S, Joe AK and Weinstein IB: Stat3 orchestrates tumor development and progression: the Achilles’ heel of head and neck cancers? Curr Cancer Drug Targets. 10:117–126. 2010.PubMed/NCBI

28. 

Takeda K, Noguchi K, Shi W, et al: Targeted disruption of the mouse STAT3 gene leads to early embryonic lethality. Proc Natl Acad Sci USA. 94:3801–3804. 1997. View Article : Google Scholar : PubMed/NCBI

29. 

Akira S: Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 19:2607–2611. 2000. View Article : Google Scholar : PubMed/NCBI

30. 

Ho JN, Kang GY, Lee SS, Kim J, Bae IH, Hwang SG and Um HD: Bcl-XL and STAT3 mediate malignant actions of gamma-irradiation in lung cancer cells. Cancer Sci. 101:1417–1423. 2010. View Article : Google Scholar : PubMed/NCBI

31. 

Hsu H-S, Lin JH, Hsu TW, Su K, Wang CW, Yang KY, et al: Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway. Lung Cancer. 75:167–177. 2012. View Article : Google Scholar : PubMed/NCBI

32. 

Floor S, van Staveren WC, Larsimont D, Dumont JE and Maenhaut C: Cancer cells in epithelial-to-mesenchymal transition and tumor propagating-cancer stem cells: distinct, overlapping or same populations. Oncogene. 30:4609–4621. 2011. View Article : Google Scholar : PubMed/NCBI

33. 

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A and Zhou AY: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI

34. 

Takebe N, Warren RQ and Ivy SP: Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res. 13:2112011. View Article : Google Scholar : PubMed/NCBI

35. 

Al-Ejeh F, Smart CE, Morrison BJ, Chenevix-Trench G, Lopez JA and Lakhani SR: Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. 32:650–658. 2011. View Article : Google Scholar : PubMed/NCBI

36. 

Blick T, Hugo H, Widodo E, Waltham M, Pinto C and Mani SA: Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24(lo/) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia. 15:235–252. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Chung SS, Giehl N, Wu Y and Vadgama JV: STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775. Int J Oncol 44: 403-411, 2014.
APA
Chung, S.S., Giehl, N., Wu, Y., & Vadgama, J.V. (2014). STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775. International Journal of Oncology, 44, 403-411. https://doi.org/10.3892/ijo.2013.2195
MLA
Chung, S. S., Giehl, N., Wu, Y., Vadgama, J. V."STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775". International Journal of Oncology 44.2 (2014): 403-411.
Chicago
Chung, S. S., Giehl, N., Wu, Y., Vadgama, J. V."STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775". International Journal of Oncology 44, no. 2 (2014): 403-411. https://doi.org/10.3892/ijo.2013.2195
Copy and paste a formatted citation
x
Spandidos Publications style
Chung SS, Giehl N, Wu Y and Vadgama JV: STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775. Int J Oncol 44: 403-411, 2014.
APA
Chung, S.S., Giehl, N., Wu, Y., & Vadgama, J.V. (2014). STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775. International Journal of Oncology, 44, 403-411. https://doi.org/10.3892/ijo.2013.2195
MLA
Chung, S. S., Giehl, N., Wu, Y., Vadgama, J. V."STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775". International Journal of Oncology 44.2 (2014): 403-411.
Chicago
Chung, S. S., Giehl, N., Wu, Y., Vadgama, J. V."STAT3 activation in HER2-overexpressing breast cancer promotes epithelial-mesenchymal transition and cancer stem cell traits Corrigendum in /10.3892/ijo.2025.5775". International Journal of Oncology 44, no. 2 (2014): 403-411. https://doi.org/10.3892/ijo.2013.2195
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team