Skip to main content

Advertisement

SpringerLink
Log in

MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling

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

Abstract

A single nucleotide polymorphism (SNP309T>G) in the intronic promoter of MDM2 was recently found to accelerate carcinogenesis in early-onset cancer cases. This cancer acceleration presumably was due to increased SP1 binding, resulting in enhanced MDM2 transcriptional activation by estrogens. We evaluated MDM2 SNP309 in 343 familial breast cancer cases with known mutation status for CHEK2 1100delC, BRCA1 and BRCA2. Cancer acceleration was indeed observed in early-onset familial breast cancer cases (diagnosed ≤ 51 years), with 16% of cases carrying the MDM2 SNP309 GG genotype as compared to 4% of late-onset cases (P = 0.029). The cancer acceleration was even more pronounced in the non-mutant familial breast cancer cases, with 17% of early-onset cases carrying MDM2 SNP309 GG as compared to 2% of late-onset cases (n = 214; P = 0.015). There was no evidence for an influence of estrogen signaling in the cancer acceleration by MDM2 SNP309, as there were no differences in the prevalence of MDM2 SNP309 GG among CHEK2 1100delC and BRCA2 mutant cases (with 90% ER-positive cancers) or BRCA1 mutant cases (10% ER-positive cancers). Nor did we observe differences in MDM2 SNP309 frequencies among 75 familial breast cancer cases of our cohort with known ER status. Overall, our data suggest that MDM2 SNP309 accelerates familial breast carcinogenesis, but that this acceleration is not influenced by estrogen signaling.

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

Similar content being viewed by others

References

  1. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P et al (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602

    Article  PubMed  CAS  Google Scholar 

  2. Vogelstein B, Lane D, Levine AJ (2000): Surfing the p53 network. Nature 408(6810):307–310

    Article  PubMed  CAS  Google Scholar 

  3. Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W et al (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110

    Article  PubMed  CAS  Google Scholar 

  4. Bond GL, Menin C, Bertorelle R, Alhorpuro P, Aaltonen LA, Levine AJ (2006) MDM2 SNP309 Accelerates colorectal tumour formation in women. J Med Genet

  5. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59

    Article  PubMed  CAS  Google Scholar 

  6. Meijers-Heijboer H, Wijnen J, Vasen H, Wasielewski M, Wagner A, Hollestelle A, Elstrodt F, van den Bos R, de Snoo A, Fat GT et al (2003) The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72(5):1308–1314

    Article  PubMed  CAS  Google Scholar 

  7. de Bock GH, Schutte M, Krol-Warmerdam EM, Seynaeve C, Blom J, Brekelmans CT, Meijers-Heijboer H, van Asperen CJ, Cornelisse CJ, Devilee P et al (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41(10):731–735

    Article  PubMed  CAS  Google Scholar 

  8. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318

    Article  PubMed  CAS  Google Scholar 

  9. Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, Tilanus-Linthorst MM, Bartels CC, Wagner A, van den Ouweland A et al (1998) Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351(9099):316–321

    Article  PubMed  CAS  Google Scholar 

  10. van de Wetering M, Barker N, Harkes IC, van der Heyden M, Dijk NJ, Hollestelle A, Klijn JG, Clevers H, Schutte M (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61(1):278–284

    PubMed  Google Scholar 

  11. Elstrodt F, Hollestelle A, Nagel JH, Gorin M, Wasielewski M, van den Ouweland A, Merajver SD, Ethier SP, Schutte M (2006) BRCA1 Mutation Analysis of 41 Human Breast Cancer Cell Lines Reveals Three New Deleterious Mutants. Cancer Res 66(1):41–45

    Article  PubMed  CAS  Google Scholar 

  12. Houlston RS, Peto J (2004) The search for low-penetrance cancer susceptibility alleles. Oncogene 23(38):6471–6476

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Funding was provided by KWF Dutch Cancer Society

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 1738, 3000 DR, Rotterdam, The Netherlands

    Marijke Wasielewski, Jord H. A. Nagel, Cecile Brekelmans, Jan G. M. Klijn, Hanne Meijers-Heijboer & Mieke Schutte

  2. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ans van den Ouweland & Hanne Meijers-Heijboer

Authors
  1. Marijke Wasielewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jord H. A. Nagel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cecile Brekelmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan G. M. Klijn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ans van den Ouweland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hanne Meijers-Heijboer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mieke Schutte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mieke Schutte.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wasielewski, M., Nagel, J.H.A., Brekelmans, C. et al. MDM2 SNP309 accelerates familial breast carcinogenesis independently of estrogen signaling. Breast Cancer Res Treat 104, 153–157 (2007). https://doi.org/10.1007/s10549-006-9407-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9407-5

Keywords

Search

Navigation