Skip to main content

Thank you for visiting 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.

TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis


Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERα and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial–mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24hi/CD49fmid luminal cell population and concomitant gain of the CD24mid/CD49fhi basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.

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

Access options

Rent or buy this article

Prices vary by article type



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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Accession codes


Gene Expression Omnibus


  1. Friedrichs N, Steiner S, Buettner R, Knoepfle G . Immunohistochemical expression patterns of AP2alpha and AP2gamma in the developing fetal human breast. Histopathology 2007; 51: 814–823.

    Article  CAS  Google Scholar 

  2. Gee JM, Eloranta JJ, Ibbitt JC, Robertson JF, Ellis IO, Williams T et al. Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti-hormone therapy and reduced patient survival. J Pathol 2009; 217: 32–41.

    Article  CAS  Google Scholar 

  3. Friedrichs N, Jager R, Paggen E, Rudlowski C, Merkelbach-Bruse S, Schorle H et al. Distinct spatial expression patterns of AP-2alpha and AP-2gamma in non-neoplastic human breast and breast cancer. Mod Pathol 2005; 18: 431–438.

    Article  CAS  Google Scholar 

  4. McPherson LA, Baichwal VR, Weigel RJ . Identification of ERF-1 as a member of the AP2 transcription factor family. Proc Natl Acad Sci USA 1997; 94: 4342–4347.

    Article  CAS  Google Scholar 

  5. Woodfield GW, Horan AD, Chen Y, Weigel RJ . TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling. Cancer Res 2007; 67: 8439–8443.

    Article  CAS  Google Scholar 

  6. Ailan H, Xiangwen X, Daolong R, Lu G, Xiaofeng D, Xi Q et al. Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells. BMC Cancer 2009; 9: 279.

    Article  Google Scholar 

  7. Delacroix L, Begon D, Chatel G, Jackers P, Winkler R . Distal ERBB2 promoter fragment displays specific transcriptional and nuclear binding activities in ERBB2 overexpressing breast cancer cells. DNA Cell Biol 2005; 24: 582–594.

    Article  CAS  Google Scholar 

  8. Bosher JM, Williams T, Hurst HC . The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl Acad Sci USA 1995; 92: 744–747.

    Article  CAS  Google Scholar 

  9. Woodfield GW, Chen Y, Bair TB, Domann FE, Weigel RJ . Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells. Genes Chromosomes Cancer 2010; 49: 948–962.

    Article  CAS  Google Scholar 

  10. Tan SK, Lin ZH, Chang CW, Varang V, Chng KR, Pan YF et al. AP-2gamma regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription. EMBO J 2011; 30: 2569–2581.

    Article  CAS  Google Scholar 

  11. Qiao Y, Zhu Y, Sheng N, Chen J, Tao R, Zhu Q et al. AP2gamma regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning. Cell Res 2012; 22: 1546–1561.

    Article  CAS  Google Scholar 

  12. Hoffman TL, Javier AL, Campeau SA, Knight RD, Schilling TF . Tfap2 transcription factors in zebrafish neural crest development and ectodermal evolution. J Exp Zool B Mol Dev Evol 2007; 308: 679–691.

    Article  Google Scholar 

  13. Jager R, Friedrichs N, Heim I, Buttner R, Schorle H . Dual role of AP-2gamma in ErbB-2-induced mammary tumorigenesis. Breast Cancer Res Treat 2005; 90: 273–280.

    Article  Google Scholar 

  14. Auman HJ, Nottoli T, Lakiza O, Winger Q, Donaldson S, Williams T . Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development. Development 2002; 129: 2733–2747.

    CAS  Google Scholar 

  15. Jager R, Schafer S, Hau-Liersch M, Schorle H . Loss of transcription factor AP-2gamma/TFAP2C impairs branching morphogenesis of the murine mammary gland. Dev Dyn 2010; 239: 1027–1033.

    Article  Google Scholar 

  16. Kao J, Salari K, Bocanegra M, Choi YL, Girard L, Gandhi J et al. Molecular profiling of breast cancer cell lines defines relevant tumor models and provides a resource for cancer gene discovery. PLoS One 2009; 4: e6146.

    Article  Google Scholar 

  17. 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 

  18. Groger CJ, Grubinger M, Waldhor T, Vierlinger K, Mikulits W . Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression. PLoS One 2012; 7: e51136.

    Article  Google Scholar 

  19. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.

    Article  CAS  Google Scholar 

  20. Guttormsen J, Koster MI, Stevens JR, Roop DR, Williams T, Winger QA . Disruption of epidermal specific gene expression and delayed skin development in AP-2 gamma mutant mice. Dev Biol 2008; 317: 187–195.

    Article  CAS  Google Scholar 

  21. Wagner KU, Wall RJ, St-Onge L, Gruss P, Wynshaw-Boris A, Garrett L et al. Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 1997; 25: 4323–4330.

    Article  CAS  Google Scholar 

  22. Kalyuga M, Gallego-Ortega D, Lee HJ, Roden DL, Cowley MJ, Caldon CE et al. ELF5 suppresses estrogen sensitivity and underpins the acquisition of antiestrogen resistance in luminal breast cancer. PLoS Biol 2012; 10: e1001461.

    Article  CAS  Google Scholar 

  23. Buchwalter G, Hickey MM, Cromer A, Selfors LM, Gunawardane RN, Frishman J et al. PDEF promotes luminal differentiation and acts as a survival factor for ER-positive breast cancer cells. Cancer Cell 2013; 23: 753–767.

    Article  CAS  Google Scholar 

  24. Bai F, Smith MD, Chan HL, Pei XH . Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation. Oncogene 2013; 32: 2715–2725.

    Article  CAS  Google Scholar 

  25. Balko JM, Miller TW, Morrison MM, Hutchinson K, Young C, Rinehart C et al. The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci USA 2012; 109: 221–226.

    Article  CAS  Google Scholar 

  26. Bernardo GM, Bebek G, Ginther CL, Sizemore ST, Lozada KL, Miedler JD et al. FOXA1 represses the molecular phenotype of basal breast cancer cells. Oncogene 2013; 32: 554–563.

    Article  CAS  Google Scholar 

  27. Carr JR, Kiefer MM, Park HJ, Li J, Wang Z, Fontanarosa J et al. FoxM1 regulates mammary luminal cell fate. Cell Rep 2012; 1: 715–729.

    Article  CAS  Google Scholar 

  28. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.

    Article  CAS  Google Scholar 

  29. dos Santos CO, Rebbeck C, Rozhkova E, Valentine A, Samuels A, Kadiri LR et al. Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells. Proc Natl Acad Sci USA 2013; 110: 7123–7130.

    Article  CAS  Google Scholar 

  30. Spanheimer PM, Askeland RW, Kulak MV, Wu T, Weigel RJ . High TFAP2C/low CD44 expression is associated with an increased rate of pathologic complete response following neoadjuvant chemotherapy in breast cancer. J Surg Res 2013; 184: 519–525.

    Article  CAS  Google Scholar 

  31. Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K . Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res 2010; 16: 876–887.

    Article  CAS  Google Scholar 

  32. Ricardo S, Vieira AF, Gerhard R, Leitao D, Pinto R, Cameselle-Teijeiro JF et al. Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol 2011; 64: 937–946.

    Article  Google Scholar 

  33. Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E et al. An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 2011; 104: 1730–1738.

    Article  CAS  Google Scholar 

  34. deConinck EC, McPherson LA, Weigel RJ . Transcriptional regulation of estrogen receptor in breast carcinomas. Mol Cell Biol 1995; 15: 2191–2196.

    Article  CAS  Google Scholar 

  35. Plante I, Stewart MK, Laird DW . Evaluation of mammary gland development and function in mouse models. J Vis Exp (e-pub ahead of print 21 July 2011; pii:2828, doi:10.3791/2828).

  36. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D et al. Purification and unique properties of mammary epithelial stem cells. Nature 2006; 439: 993–997.

    Article  CAS  Google Scholar 

  37. Smalley MJ . Isolation, culture and analysis of mouse mammary epithelial cells. Methods Mol Biol 2010; 633: 139–170.

    Article  CAS  Google Scholar 

Download references


This work was supported by the National Institutes of Health grants R01CA109294 (PI: RJW), T32CA148062 (PI: RJW), K99/R00CA158055 (PI: WZ), a Startup Fund from the Department of Pathology (PI: WZ) and by a generous gift from the Kristen Olewine Milke Breast Cancer Research Fund. PMS was supported by the NIH grant T32CA148062.

Author information

Authors and Affiliations


Corresponding author

Correspondence to R J Weigel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cyr, A., Kulak, M., Park, J. et al. TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis. Oncogene 34, 436–444 (2015).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


This article is cited by


Quick links