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FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma

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Abstract

The FOXA family of transcription factors regulates chromatin structure and gene expression especially during embryonic development. In normal breast tissue FOXA1 acts throughout mammary development; whereas in breast carcinoma its expression promotes luminal phenotype and correlates with good prognosis. However, the role of FOXA2 has not been previously studied in breast cancer. Our purpose was to analyze the expression of FOXA2 in breast cancer cells, to explore its role in breast cancer stem cells, and to correlate its mRNA expression with clinicopathological features and outcome in a series of patients diagnosed with breast carcinoma. We analyzed FOXA2 mRNA expression in a retrospective cohort of 230 breast cancer patients and in cell lines. We also knocked down FOXA2 mRNA expression by siRNA to determine the impact on cell proliferation and mammospheres formation using a cancer stem cells culture assay. In vitro studies demonstrated higher FOXA2 mRNA expression in Triple-Negative/Basal-like cells. Further, when it was knocked down, cells decreased proliferation and its capability of forming mammospheres. Similarly, FOXA2 mRNA expression was detected in 10 % (23/230) of the tumors, especially in Triple-Negative/Basal-like phenotype (p < 0.001, Fisher’s test). Patients whose tumors expressed FOXA2 had increased relapses (59 vs. 79 %, p = 0.024, log-rank test) that revealed an independent prognostic value (HR = 3.29, C.I.95 % = 1.45–7.45, p = 0.004, Cox regression). Our results suggest that FOXA2 promotes cell proliferation, maintains cancer stem cells, favors the development of Triple-Negative/Basal-like tumors, and is associated with increase relapses.

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Abbreviations

CK:

Citokeratine

CSC:

Cancer stem cell

DFS:

Disease-free survival

EGFR:

Epidermal growth factor receptor

FFPE:

Formalin-fixed paraffin-embedded

HR:

Hormonal receptor

IHC:

Immunohistochemistry

OS:

Overall survival

qRT-PCR:

Quantitative real-time PCR

References

  1. Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale A-L, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Nat Acad Sci USA 100(14):8418–8423. doi:10.1073/pnas.0932692100

    Article  PubMed Central  PubMed  Google Scholar 

  2. Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.ccr-04-0220

    Article  CAS  PubMed  Google Scholar 

  3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi:10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  4. Yeon C, Pegram M (2005) Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest New Drugs 23(5):391–409. doi:10.1007/s10637-005-2899-8

    Article  CAS  PubMed  Google Scholar 

  5. Perou CM (2012) Molecular stratification of triple-negative breast cancers. Oncologist 16(Suppl 1):61–70

    Google Scholar 

  6. Oakman C, Viale G, Di Leo A (2010) Management of triple negative breast cancer. The Breast 19(5):312–321. doi:10.1016/j.breast.2010.03.026

    Article  PubMed  Google Scholar 

  7. Criscitiello C, Azim HA, Schouten PC, Linn SC, Sotiriou C, vi13-vi18 (2012) Understanding the biology of triple-negative breast cancer. Ann Oncol 23(suppl 6):vi13–vi18. doi:10.1093/annonc/mds188

    Article  PubMed  Google Scholar 

  8. Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281. doi:10.1200/jco.2007.14.4147

    Article  PubMed  Google Scholar 

  9. Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS (2002) Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell 9(2):279–289. doi:10.1016/S1097-2765(02)00459-8

    Article  CAS  PubMed  Google Scholar 

  10. Kaestner KH (2010) The FoxA factors in organogenesis and differentiation. Curr Opin Genet Dev 20(5):527–532. doi:10.1016/j.gde.2010.06.005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Ang S-L, Rossant J (1994) HNF-3β is essential for node and notochord formation in mouse development. Cell 78(4):561–574. doi:10.1016/0092-8674(94)90522-3

    Article  CAS  PubMed  Google Scholar 

  12. Weinstein DC, Altaba ARI, Chen WS, Hoodless P, Prezioso VR, Jessell TM, Darnell JE Jr (1994) The winged-helix transcription factor HNF-3β is required for notochord development in the mouse embryo. Cell 78(4):575–588. doi:10.1016/0092-8674(94)90523-1

    Article  CAS  PubMed  Google Scholar 

  13. Kaestner KH (2005) The making of the liver: competence in the foregut endoderm and induction of liver-specific genes. Cell Cycle 4(9):1146–1148

    Article  CAS  PubMed  Google Scholar 

  14. Wan H, Dingle S, Xu Y, Besnard V, Kaestner KH, Ang S-L, Wert S, Stahlman MT, Whitsett JA (2005) Compensatory Roles of Foxa1 and Foxa2 during Lung Morphogenesis. J Biol Chem 280(14):13809–13816. doi:10.1074/jbc.M414122200

    Article  CAS  PubMed  Google Scholar 

  15. Gao N, LeLay J, Vatamaniuk MZ, Rieck S, Friedman JR, Kaestner KH (2008) Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development. Genes Dev 22(24):3435–3448. doi:10.1101/gad.1752608

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Ferri ALM, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, Ang S-L (2007) Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 134(15):2761–2769. doi:10.1242/dev.000141

    Article  CAS  PubMed  Google Scholar 

  17. Cirillo LA, McPherson CE, Bossard P, Stevens K, Cherian S, Shim EY, Clark KL, Burley SK, Zaret KS (1998) Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J 17(1):244–254. doi:10.1093/emboj/17.1.244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Besnard V, Wert SE, Hull WM, Whitsett JA (2004) Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns 5(2):193–208. doi:10.1016/j.modgep.2004.08.006

    Article  CAS  PubMed  Google Scholar 

  19. Bernardo GM, Lozada KL, Miedler JD, Harburg G, Hewitt SC, Mosley JD, Godwin AK, Korach KS, Visvader JE, Kaestner KH, Abdul-Karim FW, Montano MM, Keri RA (2010) FOXA1 is an essential determinant of ER alpha expression and mammary ductal morphogenesis. Development 137(12):2045–2054

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Badve S, Turbin D, Thorat MA, Morimiya A, Nielsen TO, Perou CM, Dunn S, Huntsman DG, Nakshatri H (2007) FOXA1 expression in breast cancer—correlation with luminal subtype A and survival. Clin Cancer Res 13(15 Pt 1):4415–4421

    Article  CAS  PubMed  Google Scholar 

  21. Thorat MA, Marchio C, Morimiya A, Savage K, Nakshatri H, Reis-Filho JS, Badve S (2008) Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis. J Clin Pathol 61(3):327–332

    Article  CAS  PubMed  Google Scholar 

  22. Wolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP (2007) FOXA1: growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer 120(5):1013–1022. doi:10.1002/ijc.22389

    Article  CAS  PubMed  Google Scholar 

  23. Habashy HO, Powe DG, Rakha EA, Ball G, Paish C, Gee J, Nicholson RI, Ellis IO (2008) Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance. Eur J Cancer 44(11):1541–1551. doi:10.1016/j.ejca.2008.04.020

    Article  CAS  PubMed  Google Scholar 

  24. Elston CW, Ellis IO (2002) Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 41(3A):154–161

    Article  CAS  PubMed  Google Scholar 

  25. Altman DG, McShane LM, Sauerbrei W, Taube SE (2012) Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): explanation and elaboration. PLoS Med 9(5):e1001216

    Article  PubMed Central  PubMed  Google Scholar 

  26. Peiro G, Adrover E, Sanchez-Tejada L, Lerma E, Planelles M, Sanchez-Paya J, Aranda FI, Giner D, Gutierrez-Avino FJ (2011) Increased insulin-like growth factor-1 receptor mRNA expression predicts poor survival in immunophenotypes of early breast carcinoma. Mod Pathol 24(2):201–208

    Article  CAS  PubMed  Google Scholar 

  27. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–527. doi:10.1016/j.ccr.2006.10.008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270. doi:10.1101/gad.1061803

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Carrasco-Garcia E, Saceda M, Grasso S, Rocamora-Reverte L, Conde M, Gomez-Martinez A, Garcia-Morales P, Ferragut JA, Martinez-Lacaci I (2011) Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines. Exp Cell Res 317(10):1476–1489. doi:10.1016/j.yexcr.2011.03.015

    Article  CAS  PubMed  Google Scholar 

  30. Laganiere J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguere V (2005) From the cover: location analysis of estrogen receptor alpha target promoters reveals that foxa1 defines a domain of the estrogen response. Proc Natl Acad Sci USA 102(33):11651–11656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25(21):2227–2241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, Fox EA, Silver PA, Brown M (2005) Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122(1):33–43

    Article  CAS  PubMed  Google Scholar 

  33. Augello MA, Hickey TE, Knudsen KE (2011) FOXA1: master of steroid receptor function in cancer. EMBO J 30(19):3885–3894

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Tang Y, Shu G, Yuan X, Jing N, Song J (2011) FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Res 21(2):316–326

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Song Y, Washington MK, Crawford HC (2010) Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res 70:2115–2125

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J, Rakha EA, Richardson AL, Schmitt FC, Tan P-H, Tse GM, Weigelt B, Ellis IO, Reis-Filho JS (2011) Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 24(2):157–167

    Article  PubMed  Google Scholar 

  37. Lawson JC, Blatch GL, Edkins AL (2009) Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat 118(2):241–254. doi:10.1007/s10549-009-0524-9

    Article  PubMed  Google Scholar 

  38. Owens TW, Naylor MJ (2013) Breast cancer stem cells. Front Physiol 4:225. doi:10.3389/fphys.2013.00225

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank Mrs Doreen Dennecker for the revision of this manuscript, and Laura Andreu for their technical assistance.

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Authors and Affiliations

  1. Research Unit, Hospital General Universitari d’Alacant, C/Pintor Baeza 12, 03010, Alacant, Spain

    Ariadna Perez-Balaguer, Fernando Ortiz-Martínez, Araceli García-Martínez, Critina Pomares-Navarro & Gloria Peiró

  2. Department of Pathology, Hospital de la Santa Creu i Sant Pau, C/Sant Quintí 87-89, 08041, Barcelona, Spain

    Enrique Lerma

  3. Pathology Department, University General Hospital of Alicante, Alicante, Spain

    Gloria Peiró

  4. Institute of Bioengineering of Catalonia, C/Baldiri Reixac, 15–21, 08028, Barcelona, Catalonia, Spain

    Ariadna Perez-Balaguer

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  1. Ariadna Perez-Balaguer
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Correspondence to Ariadna Perez-Balaguer.

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Perez-Balaguer, A., Ortiz-Martínez, F., García-Martínez, A. et al. FOXA2 mRNA expression is associated with relapse in patients with Triple-Negative/Basal-like breast carcinoma. Breast Cancer Res Treat 153, 465–474 (2015). https://doi.org/10.1007/s10549-015-3553-6

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  • DOI: https://doi.org/10.1007/s10549-015-3553-6

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