Skip to main content

Advertisement

SpringerLink
Log in

Estrogen levels act as a rheostat on p53 levels and modulate p53-dependent responses in breast cancer cell lines

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

Abstract

A large proportion of breast cancers expresses the estrogen receptor alpha (ERα) and are dependent on estrogens for their proliferation and survival. The tumor suppressor TP53 encodes the p53 protein, an important mediator of the anti-proliferative and apoptotic effects of several treatments used for breast cancer. A significant proportions of breast tumors (20–30%) carry mutations in TP53 gene and these mutations are associated with poor survival and poor response to several types of chemotherapeutic treatments. While there is mounting evidence for functional interactions between p53 and ERα pathways in breast and other tissues, the impact of these interactions on response to chemotherapy and anti-hormone treatments remain largely unknown. Here, using estrogen-dependent breast cancer cell lines with different p53 status, we show that estrogens, through ERα, influence p53 protein levels and activities. Estrogen deprivation reduced, while estradiol increased p53 levels, in a time and dose-dependent manner. Both wild-type and endogenously expressed mutant p53 proteins were affected. This reduction in p53 protein levels resulted in reduced p53-dependent responses induced by DNA damage in p53 wild-type cells, lowering the capacity of doxorubicine to induce apoptosis. The p53 response appeared to be quantitatively but not qualitatively affected. These results suggest that ERα activity is required for a strong p53 response in estrogen-dependent breast cancer cells. These results are in line with previous observations that we made in a clinical series, where a larger effect of TP53 mutation status was found for patient survival in cases with progesterone receptor positive status, a marker of a functional ERα pathway. It would thus be important to further characterize the influence of ERα pathway on the predictive value of TP53 mutation status in specifically designed clinical trials, as it may open perspectives for improving breast cancer 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

Similar content being viewed by others

References

  1. Levine AJ, Momand J, Finlay CA (1991) The p53 tumour suppressor gene. Nature 351:453–456

    Article  CAS  PubMed  Google Scholar 

  2. Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137

    Article  CAS  PubMed  Google Scholar 

  3. Olivier M, Hainaut P, Borresen-Dale A (2005) Prognostic and predictive value of TP53 mutations in human cancer. In: Hainaut P, Wiman K (eds) 25 years of p53 research. Springer, pp 321–338

  4. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA (2007) Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87:905–931

    Article  CAS  PubMed  Google Scholar 

  5. Cheskis BJ, Greger JG, Nagpal S, Freedman LP (2007) Signaling by estrogens. J Cell Physiol 213:610–617

    Article  CAS  PubMed  Google Scholar 

  6. Santen RJ, Fan P, Zhang Z, Bao Y, Song RX, Yue W (2009) Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids 74:586–594

    Article  CAS  PubMed  Google Scholar 

  7. Duong V, Boulle N, Daujat S, Chauvet J, Bonnet S, Neel H, Cavailles V (2007) Differential regulation of estrogen receptor alpha turnover and transactivation by Mdm2 and stress-inducing agents. Cancer Res 67:5513–5521

    Article  CAS  PubMed  Google Scholar 

  8. Liu G, Schwartz JA, Brooks SC (2000) Estrogen receptor protects p53 from deactivation by human double minute-2. Cancer Res 60:1810–1814

    CAS  PubMed  Google Scholar 

  9. Hurd C, Dinda S, Khattree N, Moudgil VK (1999) Estrogen-dependent and independent activation of the P1 promoter of the p53 gene in transiently transfected breast cancer cells. Oncogene 18:1067–1072

    Article  CAS  PubMed  Google Scholar 

  10. Moudgil VK, Dinda S, Khattree N, Jhanwar S, Alban P, Hurd C (2001) Hormonal regulation of tumor suppressor proteins in breast cancer cells. J Steroid Biochem Mol Biol 76:105–117

    Article  CAS  PubMed  Google Scholar 

  11. Shirley SH, Rundhaug JE, Tian J, Cullinan-Ammann N, Lambertz I, Conti CJ, Fuchs-Young R (2009) Transcriptional regulation of estrogen receptor-alpha by p53 in human breast cancer cells. Cancer Res 69:3405–3414

    Article  CAS  PubMed  Google Scholar 

  12. Angeloni SV, Martin MB, Garcia-Morales P, Castro-Galache MD, Ferragut JA, Saceda M (2004) Regulation of estrogen receptor-alpha expression by the tumor suppressor gene p53 in MCF-7 cells. J Endocrinol 180:497–504

    Article  CAS  PubMed  Google Scholar 

  13. Liu G, Schwartz JA, Brooks SC (1999) p53 down-regulates ER-responsive genes by interfering with the binding of ER to ERE. Biochem Biophys Res Commun 264:359–364

    Article  CAS  PubMed  Google Scholar 

  14. Jeffy BD, Hockings JK, Kemp MQ, Morgan SS, Hager JA, Beliakoff J, Whitesell LJ, Bowden GT, Romagnolo DF (2005) An estrogen receptor-alpha/p300 complex activates the BRCA-1 promoter at an AP-1 site that binds Jun/Fos transcription factors: repressive effects of p53 on BRCA-1 transcription. Neoplasia 7:873–882

    Article  CAS  PubMed  Google Scholar 

  15. Jin W, Chen Y, Di GH, Miron P, Hou YF, Gao H, Shao ZM (2008) Estrogen Receptor (ER) beta or p53 attenuates ER{alpha}-mediated transcriptional activation on the BRCA2 promoter. J Biol Chem 283:29671–29680

    Article  CAS  PubMed  Google Scholar 

  16. Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK, Das GM (2006) Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chem 281:9837–9840

    Article  CAS  PubMed  Google Scholar 

  17. Lewandowski SA, Thiery J, Jalil A, Leclercq G, Szczylik C, Chouaib S (2005) Opposite effects of estrogen receptors alpha and beta on MCF-7 sensitivity to the cytotoxic action of TNF and p53 activity. Oncogene 24:4789–4798

    Article  CAS  PubMed  Google Scholar 

  18. Molinari AM, Bontempo P, Schiavone EM, Tortora V, Verdicchio MA, Napolitano M, Nola E, Moncharmont B, Medici N, Nigro V, Armetta I, Abbondanza C, Puca GA (2000) Estradiol induces functional inactivation of p53 by intracellular redistribution. Cancer Res 60:2594–2597

    CAS  PubMed  Google Scholar 

  19. Menendez D, Inga A, Snipe J, Krysiak O, Schonfelder G, Resnick MA (2007) A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Mol Cell Biol 27:2590–2600

    Article  CAS  PubMed  Google Scholar 

  20. Lowe SW (1995) Cancer therapy and p53. Curr Opin Oncol 7:547–553

    Article  CAS  PubMed  Google Scholar 

  21. Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Borresen-Dale AL (2006) The clinical value of somatic TP53 gene mutations in 1, 794 patients with breast cancer. Clin Cancer Res 12:1157–1167

    Article  CAS  PubMed  Google Scholar 

  22. Shaulian E, Zauberman A, Ginsberg D, Oren M (1992) Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol 12:5581–5592

    CAS  PubMed  Google Scholar 

  23. Salvat C, Aquaviva C, Jariel-Encontre I, Ferrara P, Pariat M, Steff AM, Carillo S, Piechaczyk M (1999) Are there multiple proteolytic pathways contributing to c-Fos, c-Jun and p53 protein degradation in vivo? Mol Biol Rep 26:45–51

    Article  CAS  PubMed  Google Scholar 

  24. Nawaz Z, Lonard DM, Dennis AP, Smith CL, O’Malley BW (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA 96:1858–1862

    Article  CAS  PubMed  Google Scholar 

  25. Wijayaratne AL, McDonnell DP (2001) The human estrogen receptor-alpha is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists, and selective estrogen receptor modulators. J Biol Chem 276:35684–35692

    Article  CAS  PubMed  Google Scholar 

  26. Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3:973–982

    Article  CAS  PubMed  Google Scholar 

  27. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299–303

    Article  CAS  PubMed  Google Scholar 

  28. Schiff R, Massarweh S, Shou J, Osborne CK (2003) Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 9:447S–454S

    CAS  PubMed  Google Scholar 

  29. Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, Jerry DJ (2005) Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene 24:6345–6353

    CAS  PubMed  Google Scholar 

  30. Dunphy KA, Blackburn AC, Yan H, O’Connell LR, Jerry DJ (2008) Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53 ± mice. Breast Cancer Res 10:R43

    Article  PubMed  Google Scholar 

  31. Guillot C, Falette N, Courtois S, Voeltzel T, Garcia E, Ozturk M, Puisieux A (1996) Alteration of p53 damage response by tamoxifen treatment. Clin Cancer Res 2:1439–1444

    CAS  PubMed  Google Scholar 

  32. Adhikari AS, Iwakuma T (2009) Mutant p53 gain of oncogenic function: in vivo evidence, mechanism of action and its clinical implications. Fukuoka Igaku Zasshi 100:217–228

    CAS  PubMed  Google Scholar 

  33. Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713

    CAS  PubMed  Google Scholar 

  34. Terzian T, Suh YA, Iwakuma T, Post SM, Neumann M, Lang GA, Van Pelt CS, Lozano G (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22:1337–1344

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study has been supported by a grant from the Association for International Cancer Research. We thank Ke-Seay Smoth for her technical help.

Author information

Authors and Affiliations

  1. Molecular Carcinogenesis Group, International Agency for Research on Cancer, Lyon, France

    Lynnette Fernández-Cuesta, Suresh Anaganti, Pierre Hainaut & Magali Olivier

Authors
  1. Lynnette Fernández-Cuesta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suresh Anaganti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Hainaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Magali Olivier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Magali Olivier.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 290 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernández-Cuesta, L., Anaganti, S., Hainaut, P. et al. Estrogen levels act as a rheostat on p53 levels and modulate p53-dependent responses in breast cancer cell lines. Breast Cancer Res Treat 125, 35–42 (2011). https://doi.org/10.1007/s10549-010-0819-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-0819-x

Keywords

Search

Navigation