Skip to main content

Advertisement

SpringerLink
Log in

Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells

  • Preclinical Study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Zinc-finger enhancer binding protein (ZEB1) is a transcription factor involved in the progression of cancer primarily through promoting epithelial to mesenchymal transition (EMT). ZEB1 represses the expression of E-cadherin by binding to E-box sequences in the promoter, thus decreasing epithelial differentiation. We show that ZEB1 and androgen receptor (AR) cross-talk in triple negative breast cancer cell lines. Chromatin immunoprecipitation analysis demonstrates that ZEB1 binds directly to the E-box located in the AR promoter. ZEB1 suppression by stably transfecting shRNA in a triple negative breast cancer cell line resulted in a decrease of AR mRNA, protein, and AR downstream targets. ZEB1 knockdown in triple negative breast cancer cells sensitized the cells to bicalutamide by reducing migration compared to the control cells. Conversely, blockade of AR signaling with bicalutamide resulted in a suppression of ZEB1 protein expression in two triple negative breast cancer cell lines. Furthermore, using a breast cancer tissue microarray, a majority of triple negative breast cancers exhibit positive staining for both ZEB1 and AR. Taken together, these results indicate that ZEB1 and AR regulate each other to promote cell migration in triple negative breast cancer cells.

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
Fig. 6

Similar content being viewed by others

References

  1. Brys M, Wojcik M, Makowska H, Krajewska W (2002) Androgen receptor status in female breast cancer: RT-PCR and western blot studies. J Cancer Res Clin Oncol 128:85–90

    Article  CAS  PubMed  Google Scholar 

  2. Davidson N, Lippman M (1989) The role of estrogens in growth regulation of breast cancer. Crit Rev Oncog 1:89–111

    CAS  PubMed  Google Scholar 

  3. Platet N, Cathiard A, Gleizes M, Garcia M (2004) Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol 51:55–67

    Article  PubMed  Google Scholar 

  4. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF et al (2005) Results of the ATAC (arimidex, tamoxifen, alone or in combination) trial after completion of 5 years of adjuvant treatment for breast cancer. Lancet 365:60–62

    Article  CAS  PubMed  Google Scholar 

  5. Isola J (1993) Immunohistochemical demonstration of androgen receptor in breast cancer and its relationship to other prognostic factors. J Pathol 170:31–35

    Article  CAS  PubMed  Google Scholar 

  6. Diaz-Chico B, Rodriguez F, Gonzalez A, Ramirez R, Bilbao C et al (2007) Androgens and androgen receptors in breast cancer. Steroid Biochem Mol Biol 105:1–15

    Article  Google Scholar 

  7. Birrell S, Hall R, Tilley W (1998) Role of androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia 3:95–103

    Article  CAS  PubMed  Google Scholar 

  8. Zhu X, Li H, Liu JP, Funder JW (1999) Androgen stimulates mitogen-activated protein kinase in human breast cancer cells. Mol Cell Endocrinol 152:199–206

    Article  CAS  PubMed  Google Scholar 

  9. Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, Tilley WD (1995) Androgens induced divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol 52:459–467

    Article  CAS  PubMed  Google Scholar 

  10. Doane AS, Danso M, Lal P, Donaton M, Zhang L, Hudis C, Gerald W et al (2006) An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene 25:3994–4008

    Article  CAS  PubMed  Google Scholar 

  11. Wong YC, Xie B (2001) The role of androgens I mammary carcinogenesis. Ital J Anat Embryol 106:111–115

    CAS  PubMed  Google Scholar 

  12. Boccuzzi G, Tamagno E, Brignardello E et al (1995) Growth inhibition of DMBA-induced rat mammary carcinomas by the antiandrogen flutamide. J Cancer Res Clin Oncol 121:150–154

    Article  CAS  PubMed  Google Scholar 

  13. Naderi A, Hughes-Davies L (2008) A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia 10:542–548

    CAS  PubMed  Google Scholar 

  14. Eger A, Aigner K, Sonderegger S et al (2005) Delta EF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24:2375–2385

    Article  CAS  PubMed  Google Scholar 

  15. Ohira T, Gemmill R, Ferguson K et al (2003) WNT7a induces E-cadherin in lung cancer cells. PNAS 100:10429–10434

    Article  CAS  PubMed  Google Scholar 

  16. Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S et al (2006) A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131:830–840

    Article  CAS  PubMed  Google Scholar 

  17. Vincent-Salomon A, Theiry JP (2003) Epithelial-mesenchymal transition in breast cancer development. Breast Cancer Res 5:101–106

    Article  CAS  PubMed  Google Scholar 

  18. Chua H, Bhat-Nakshatri P, Clare S, Morimiya A, Badve S, Nakshatri H (2007) NF-κB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB1 and ZEB2. Oncogene 26:711–724

    Google Scholar 

  19. Graham TR, Zhau H, Odero-Marah V, Osunkoya A, Kimbro K et al (2008) Insulin-like growth factor-I-dependent upregulation of ZEB1 drives epithelial to mesenchymal transition in human prostate cancer cells. Cancer Res 68:2479–2488

    Article  CAS  PubMed  Google Scholar 

  20. Postigo A, Dean D (1997) ZEB, a vertebrate homolog of Drosophila Zfh-1, is a negative regulator of muscle differentiation. EMBO J 16:3935–3943

    Article  CAS  PubMed  Google Scholar 

  21. Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K et al (2008) The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 68:537–544

    Article  CAS  PubMed  Google Scholar 

  22. Spoelstra N, Manning N, Higashi Y, Darling D, Singh M, Shroyer K et al (2006) The transcription factor ZEB1 is aberrantly expressed in aggressive uterine cancers. Cancer Res 66:3893–3902

    Article  CAS  PubMed  Google Scholar 

  23. Hope I, Mahadevan S, Struhl K (1998) Structural and functional characterization of the short acidic transcriptional activation domain of yeast GCN4 protein. Nature 333:635–640

    Article  Google Scholar 

  24. Seipel K, Georgiev O, Schaffner W (1992) Different activation domains stimulate transcription from remote (“enhancer”) and proximal (“promoter”) positions. EMBO J 11:4961–4968

    CAS  PubMed  Google Scholar 

  25. Aigner K, Dampier B, Descovich L et al (2007) The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26:1–10

    Article  Google Scholar 

  26. Wang F, Sloss C, Zhang X, Lee SW, Cusack J (2007) Membrane-bound heparin-binding epidermal growth factor like growth factor regulates E-cadherin expression in pancreatic carcinoma cells. Cancer Res 67:8486–8493

    Article  CAS  PubMed  Google Scholar 

  27. Sharma D, Fondell JD. (2002) Ordered recruitment of histone acetyltransferases and the TRAP/mediator complex to thyroid hormone-responsive promoters in vivo. Proc Natl Acad Sci 99:7394–7399

    Article  Google Scholar 

  28. Hall R, Clements J, Birrell S, Tilley W (1998) Prostate-specific antigen and gross cystic disease fluid protein-15 are co-expressed in androgen receptor-positive breast tumours. Br J Cancer 78:360–365

    CAS  PubMed  Google Scholar 

  29. DiMonaco M, Brignardello E, Leonardi L, Gatto V, Bocuzzi G (1995) Inhibitory effect of hydroxyflutamide plus tamoxifen on oestradiol-induced growth of MCF-7 breast cancer cells. J Cancer Res Clin Oncol 121:710–714

    Article  CAS  Google Scholar 

  30. Richer J, Jacobsen B, Manning N, Abel M, Wolf D, Horwitz K (2002) Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J Biol Chem 277:5209–5218

    Article  CAS  PubMed  Google Scholar 

  31. Chamberlain EM, Sanders MM (1999) Identification of the novel player deltaEF1 in estrogen transcriptional cascades. Mol Cell Biol 19:3600–3609

    CAS  PubMed  Google Scholar 

  32. Singh M, Spoelstra N, Jean A, Howe E, Torkko K, Clark H, Darling D, Shroyer K, Horwitz K, Broaddus R, Richer J (2008) ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease. Mod Pathol 21:1–12

    Article  Google Scholar 

  33. Dillner N, Sanders M (2004) Transcriptional activation by the zinc-finger homeodomain protein delta EF1 in estrogen signaling cascades. DNA Cell Biol 23:25–34

    Article  CAS  PubMed  Google Scholar 

  34. Lazarova DL, Bordonaro M, Sartorelli AC (2001) Transcriptional regulation of the vitamin D3 receptor gene by ZEB. Cell Growth Differ 12:319–326

    CAS  PubMed  Google Scholar 

  35. Sekido R, Murai K, Funashashi J, Kamachi Y, Fujisawa A (1997) Two mechanisms in the action of repressor δEF1: binding site competition with an activator and active repression. Genes Cells 2:771–783

    Article  CAS  PubMed  Google Scholar 

  36. Anose B, LaGoo L, Schwendinger J (2008) Characterization of androgen regulation of ZEB and PSA in 22RV1 prostate cancer cells. Adv Exp Med Biol 617:541–546

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Wilbur and Hilda Glenn Foundation (R. O’Regan); Georgia Cancer Coalition (R. O’Regan); National Cancer Institute Center of Cancer Nanotechnology Excellence CA119338 (R. O’Regan); BC-030963 DOD CDMRP, BCRP (D. Sharma); BCTR-0503526 Susan G Komen for the Cure (D. Sharma).

Author information

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, 1701 Uppergate Drive, WCI Building C, Atlanta, GA, 30322, USA

    Tisheeka R. Graham, Rami Yacoub, LaTonia Taliaferro-Smith, Tongrui Liu, K. Sean Kimbro, Dipali Sharma & Ruth M. O’Regan

  2. Department of Pathology and Urology, Emory University, Atlanta, GA, 30322, USA

    Adeboye O. Osunkoya

  3. Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA

    Valerie A. Odero-Marah

Authors
  1. Tisheeka R. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rami Yacoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. LaTonia Taliaferro-Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adeboye O. Osunkoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valerie A. Odero-Marah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tongrui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Sean Kimbro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dipali Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ruth M. O’Regan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ruth M. O’Regan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Graham, T.R., Yacoub, R., Taliaferro-Smith, L. et al. Reciprocal regulation of ZEB1 and AR in triple negative breast cancer cells. Breast Cancer Res Treat 123, 139–147 (2010). https://doi.org/10.1007/s10549-009-0623-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0623-7

Keywords

Search

Navigation