Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling

Oncogene volume 31, pages 4798–4802 (2012)Cite this article

Subjects

Abstract

Human basal-like breast cancer (BLBC) is an enigmatic and aggressive malignancy with a poor prognosis. There is an urgent need to identify therapeutic targets for BLBC, because current treatment modalities are limited and not effective. The forkhead box transcription factor FOXC1 has recently been identified as a critical functional biomarker for BLBC. However, how it orchestrates BLBC cells was not clear. Here we show that FOXC1 activates the transcription factor nuclear factor-κB (NF-κB) in BLBC cells by increasing p65/RelA protein stability. High NF-κB activity has been associated with estrogen receptor-negative breast cancer, particularly BLBC. The effect of FOXC1 on p65/RelA protein stability is mediated by increased expression of Pin1, a peptidyl-prolyl isomerase. FOXC1 requires NF-κB for its regulation of cell proliferation, migration and invasion. Notably, FOXC1 overexpression renders breast cancer cells more susceptible to pharmacological inhibition of NF-κB. These results suggest that BLBC cells may rely on FOXC1-driven NF-κB signaling. Interventions of this pathway may provide modalities for the treatment of BLBC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Dairkee SH, Puett L, Hackett AJ . Expression of basal and luminal epithelium-specific keratins in normal, benign, and malignant breast tissue. J Natl Cancer Inst 1988; 80: 691–695.

    Article  CAS  Google Scholar 

  2. Wetzels RHW, Holland R, Haelst UJGMv, Lane EB, Leigh IM, Ramaekers FCS . Detection of basement membrane components and basal cell keratin 14 in noninvasive and invasive carcinomas of the breast. Am J Pathol 1989; 134: 571–579.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

    Article  CAS  Google Scholar 

  4. Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 2007; 9: R65.

    Article  Google Scholar 

  5. Rakha EA, Reis-Filho JS, Ellis IO . Basal-like breast cancer: a critical review. J Clin Oncol 2008; 26: 2568–2581.

    Article  Google Scholar 

  6. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: 2492–2502.

    Article  CAS  Google Scholar 

  7. Seewaldt VL, Scott V . Images in clinical medicine. Rapid progression of basal-type breast cancer. N Engl J Med 2007; 356: e12.

    Article  Google Scholar 

  8. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol 2006; 19: 264–271.

    Article  CAS  Google Scholar 

  9. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J . Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 2008; 68: 989–997.

    Article  CAS  Google Scholar 

  10. Collett K, Stefansson IM, Eide J, Braaten A, Wang H, Eide GE et al. A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors. Cancer Epidemiol Biomarkers Prev 2005; 14: 1108–1112.

    Article  CAS  Google Scholar 

  11. Dejeux E, Ronneberg JA, Solvang H, Bukholm I, Geisler S, Aas T 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  Google Scholar 

  12. Ray PS, Wang J, Qu Y, Sim MS, Shamonki J, Bagaria SP et al. FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 2010; 70: 3870–3876.

    Article  CAS  Google Scholar 

  13. Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J 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 U S A 2010; 107: 15449–15454.

    Article  CAS  Google Scholar 

  14. Nishimura DY, Swiderski RE, Alward WL, Searby CC, Patil SR, Bennet SR et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet 1998; 19: 140–147.

    Article  CAS  Google Scholar 

  15. 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: 985–996.

    Article  CAS  Google Scholar 

  16. Mears AJ, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet 1998; 63: 1316–1328.

    Article  CAS  Google Scholar 

  17. Kidson SH, Kume T, Deng K, Winfrey V, Hogan BL . The forkhead/winged-helix gene, Mf1, is necessary for the normal development of the cornea and formation of the anterior chamber in the mouse eye. Dev Biol 1999; 211: 306–322.

    Article  CAS  Google Scholar 

  18. Smith RS, Zabaleta A, Kume T, Savinova OV, Kidson SH, Martin JE et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet 2000; 9: 1021–1032.

    Article  CAS  Google Scholar 

  19. Moulder SL . Does the PI3K pathway play a role in basal breast cancer? Clin Breast Cancer 2010; 10: S66–S71.

    Article  Google Scholar 

  20. Rexer BN, Ghosh R, Arteaga CL . Inhibition of PI3K and MEK: it is all about combinations and biomarkers. Clin Cancer Res 2009; 15: 4518–4520.

    Article  CAS  Google Scholar 

  21. Lu S, Simin K, Khan A, Mercurio AM . Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin Cancer Res 2008; 14: 1050–1058.

    Article  CAS  Google Scholar 

  22. Lee CW, Simin K, Liu Q, Plescia J, Guha M, Khan A et al. A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 2008; 10: R97.

    Article  Google Scholar 

  23. Yamaguchi N, Ito T, Azuma S, Ito E, Honma R, Yanagisawa Y 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: 1668–1674.

    Article  CAS  Google Scholar 

  24. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet Jr RJ, Sledge Jr GW . Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 1997; 17: 3629–3639.

    Article  CAS  Google Scholar 

  25. Biswas DK, Iglehart JD . Linkage between EGFR family receptors and nuclear factor kappaB (NF-kappaB) signaling in breast cancer. J Cell Physiol 2006; 209: 645–652.

    Article  CAS  Google Scholar 

  26. Gershtein ES, Scherbakov AM, Platova AM, Tchemeris GY, Letyagin VP, Kushlinskii NE . The expression and DNA-binding activity of NF-kappaB nuclear transcription factor in the tumors of patients with breast cancer. Bull Exp Biol Med 2010; 150: 71–74.

    Article  CAS  Google Scholar 

  27. Peng SL . Interplay between the NF-kappaB and forkhead transcription factors. Cell Death Differ 2005; 12: 699–701.

    Article  CAS  Google Scholar 

  28. Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G et al. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 2003; 12: 1413–1426.

    Article  CAS  Google Scholar 

  29. Lu KP . Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics. Cancer Cell 2003; 4: 175–180.

    Article  CAS  Google Scholar 

  30. Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V et al. Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1. Embo J 2001; 20: 3459–3472.

    Article  CAS  Google Scholar 

  31. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 2006; 10: 515–527.

    Article  CAS  Google Scholar 

  32. Hoeflich KP, O’Brien C, Boyd Z, Cavet G, Guerrero S, Jung K et al. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin Cancer Res 2009; 15: 4649–4664.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Yixian Zheng for the HA-ubiquitin plasmid, Fred Miller for 4T1 breast cancer cells, Inder M Verma for IKK double-knockout MEFs, Amer A Beg for p65-null MEFs, and Dave Hoon and Myles Cabot for technical support. This work was supported by National Institutes of Health (CA151610), QVC and the Fashion Footwear Association of New York Charitable Foundation, Associates for Breast & Prostate Cancer Studies, and the Avon Foundation (02-2010-068) to XC.

Author information

Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    J Wang & X Cui

  2. Department of Surgical Oncology, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    P S Ray, S P Bagaria & A E Giuliano

  3. Department of Biostatistics, John Wayne Cancer Institute, Saint John's Health Center, Santa Monica, CA, USA

    M-S Sim

  4. Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    X Z Zhou & K P Lu

  5. Department of Pharmacology and Chemical Biology, Womens Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    A V Lee

  6. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    X Lin

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

    X Cui

Authors
  1. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P S Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M-S Sim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Z Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K P Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A V Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S P Bagaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A E Giuliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to X Cui.

Ethics declarations

Competing interests

Dr Wang, Dr Ray, Dr Bagaria and Dr Cui are named inventors on patent applications regarding the role of FOXC1 in cancer.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Ray, P., Sim, MS. et al. FOXC1 regulates the functions of human basal-like breast cancer cells by activating NF-κB signaling. Oncogene 31, 4798–4802 (2012). https://doi.org/10.1038/onc.2011.635

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.635

Keywords

Search

Advanced search

Quick links