Skip to main content

Advertisement

SpringerLink
Log in

FOXC1 is a Critical Mediator of EGFR Function in Human Basal-like Breast Cancer

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Human basal-like breast cancer (BLBC) has a poor prognosis and is often identified by expression of the epidermal growth factor receptor (EGFR). BLBC remains a major clinical challenge because its pathogenesis is not well understood, thus hindering efforts to develop targeted therapies. Recent data implicate the forkhead box C1 (FOXC1) transcription factor as an important prognostic biomarker and functional regulator of BLBC, but its regulatory mechanism and impact on BLBC tumorigenesis remain unclear.

Methods

The association between FOXC1 and EGFR expression in human breast cancer was examined by immunohistochemistry in formalin-fixed tissues and analysis of the TCGA database. The regulation of FOXC1 by EGFR activation was investigated in MDA-MB-468 cells using immunoblotting, qRT-PCR, and luciferase activity assays. This EGFR effect on FOXC1 expression was confirmed using the MDA-MB-468 xenograft model.

Results

Both FOXC1 mRNA and protein levels significantly correlated with EGFR expression in human breast tumors. EGFR activation induced FOXC1 transcription through the ERK and Akt pathways in BLBC. EGFR inhibition in vivo reduced FOXC1 expression in xenograft tumors. We also found that FOXC1 knockdown impaired the effects of EGF on BLBC cell proliferation, migration, and invasion.

Conclusions

Our findings uncover a novel EGFR-FOXC1 signaling axis critical for BLBC cell functions, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26(15):2568–81.

    Article  PubMed  Google Scholar 

  2. Batra SK, Castelino-Prabhu S, Wikstrand CJ, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 1995;6(10):1251–9.

    CAS  PubMed  Google Scholar 

  3. Smid M, Wang Y, Zhang Y, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res. 2008;68(9):3108–14.

    Article  CAS  PubMed  Google Scholar 

  4. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat. rev. Cancer. 2007;7(11):847–59.

    Article  CAS  PubMed  Google Scholar 

  5. Kume T, Deng KY, Winfrey V, Gould DB, Walter MA, Hogan BL. The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell. 1998;93(6):985–96.

    Article  CAS  PubMed  Google Scholar 

  6. Bloushtain-Qimron N, Yao J, Snyder EL, et al. Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci USA. 2008;105(37):14076–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Ray PS, Wang J, Qu Y, et al. FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res. 2010;70(10):3870–6.

    Article  CAS  PubMed  Google Scholar 

  8. Taube JH, Herschkowitz JI, Komurov K, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 2010;107(35):15449–54.

    Article  CAS  Google Scholar 

  9. Xia L, Huang W, Tian D, et al. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 2012;56:1782–91.

  10. Peraldo-Neia C, Migliardi G, Mello-Grand M, et al. Epidermal growth factor receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer. 2011;11:31.

  11. Wang L, Gu F, Liu CY, Wang RJ, Li J, Xu JY. High level of FOXC1 expression is associated with poor prognosis in pancreatic ductal adenocarcinoma. Tumour Biol. Dec 16 2012.

  12. Wei LX, Zhou RS, Xu HF, Wang JY, Yuan MH. High expression of FOXC1 is associated with poor clinical outcome in non-small cell lung cancer patients. Tumour Biol. 2012.

  13. Ray PS, Bagaria SP, Wang J, et al. Basal-like breast cancer defined by FOXC1 expression offers superior prognostic value: a retrospective immunohistochemical study. Ann Surg Oncol. 2011;18(13):3839–47.

    Article  PubMed  Google Scholar 

  14. Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Tkocz D, Crawford NT, Buckley NE, et al. BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers. Oncogene. 2012;31(32):3667–78.

    Article  CAS  PubMed  Google Scholar 

  16. Andre F, Job B, Dessen P, et al. Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 2009;15(2):441–51.

    Article  CAS  PubMed  Google Scholar 

  17. Heideman MR, Hynes NE. AXL/epidermal growth factor receptor (EGFR) complexes in breast cancer: culprits for resistance to EGFR inhibitors? Breast Cancer Res. 2013;15(5):315.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367-74.

    Article  CAS  PubMed  Google Scholar 

  19. TCGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.

  20. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–16.

    Article  CAS  PubMed  Google Scholar 

  21. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16(1):103-19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Balko JM, Cook RS, Vaught DB, et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med. 2012;18(7):1052–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Hoeflich KP, O’Brien C, Boyd Z, et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res. 2009;15(14):4649–64.

    Article  CAS  PubMed  Google Scholar 

  24. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486(7403):405–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nakatani K, Thompson DA, Barthel A, et al. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem. 1999;274(31):21528–32.

    Article  CAS  PubMed  Google Scholar 

  26. Chen HZ, Tsai SY, Leone G. Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer. 2009;9(11):785–97.

    CAS  Google Scholar 

  27. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–44.

    Article  CAS  Google Scholar 

  28. Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Gen. 1998;63(5):1316–28.

    Article  CAS  Google Scholar 

  29. Cui X, Kim HJ, Kuiatse I, Kim H, Brown PH, Lee AV. Epidermal growth factor induces insulin receptor substrate-2 in breast cancer cells via c-Jun NH(2)-terminal kinase/activator protein-1 signaling to regulate cell migration. Cancer Res. 2006;66(10):5304–13.

    Article  CAS  PubMed  Google Scholar 

  30. Page-McCaw A, Ewald AJ, Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 2007;8(3):221–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Sizemore ST, Keri RA. The forkhead box transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J Biol Chem. 2012;287(29):24631–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Muggerud AA, Ronneberg JA, Warnberg F, et al. Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer. Breast Cancer Res. 2010;12(1):R3.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Dejeux E, Ronneberg JA, Solvang H, et al. DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol Cancer. 2010;9:68.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Bagaria SP, Ray PS, Wang J, et al. Prognostic value of basal phenotype in HER2-overexpressing breast cancer. Ann Surg Oncol. 2012;19(3):935–40.

    Article  PubMed  Google Scholar 

  35. Haughian JM, Pinto MP, Harrell JC, et al. Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proc Natl Acad Sci USA. 2012;109(8):2742–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17(7):3629–39.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Yamaguchi N, Ito T, Azuma S, et al. Constitutive activation of nuclear factor-kappaB is preferentially involved in the proliferation of basal-like subtype breast cancer cell lines. Cancer Sci. 2009;100(9):1668–74.

    Article  CAS  PubMed  Google Scholar 

  38. Jiang T, Grabiner B, Zhu Y, et al. CARMA3 is crucial for EGFR-Induced activation of NF-kappaB and tumor progression. Cancer Res. 2011;71(6):2183-92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Yang W, Xia Y, Cao Y, et al. EGFR-induced and PKCepsilon monoubiquitylation-dependent NF-kappaB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell. 2012;48(5):771-84.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Burness ML, Grushko TA, Olopade OI. Epidermal growth factor receptor in triple-negative and basal-like breast cancer: promising clinical target or only a marker? Cancer J. 2010;16(1):23-32.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We thank Guifa Li for the FOXC1 promoter construct. This work was supported by National Institutes of Health (CA151610), the Avon Foundation (02-2010-068), David Salomon Translational Breast Cancer Research Fund, and the Fashion Footwear Charitable Foundation of New York, Inc. to XC and the State Key Development Program for Basic Research of China (2011CB707705) and the Science and Technology Program of Guangdong (2010B031600133, 2011B031800323) to YC.

Conflict of interest

XC is a named inventor on patent applications filed relevant to the role of FOXC1 in cancer. The other authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Yanli Jin PhD, Bingchen Han PhD, Armando E. Giuliano MD & Xiaojiang Cui PhD

  2. Department of Obstetrics and Gynecology, Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Ruprecht Wiedemeyer PhD, Sandra Orsulic PhD, Beth Y. Karlan MD & Xiaojiang Cui PhD

  3. Department of Pathology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Shikha Bose MD

  4. Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital, Shantou University Medical College, Shantou, Guangdong, China

    Jiongyu Chen BS & Yukun Cui PhD

  5. Department of Biostatistics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Xiao Zhang PhD

Authors
  1. Yanli Jin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bingchen Han PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiongyu Chen BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruprecht Wiedemeyer PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandra Orsulic PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shikha Bose MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao Zhang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beth Y. Karlan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Armando E. Giuliano MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukun Cui PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaojiang Cui PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yukun Cui PhD or Xiaojiang Cui PhD.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 922 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jin, Y., Han, B., Chen, J. et al. FOXC1 is a Critical Mediator of EGFR Function in Human Basal-like Breast Cancer. Ann Surg Oncol 21 (Suppl 4), 758–766 (2014). https://doi.org/10.1245/s10434-014-3980-3

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-014-3980-3

Keywords

Search

Navigation