Skip to main content

Thank you for visiting nature.com. 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.

  • Review
  • Published:

A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans

Abstract

Cancer biology finds itself in a post-genomic era and the hopes of using inherited genetic variants to improve prevention and treatment strategies are widespread. One of the largest types of inherited genetic variation is the single nucleotide polymorphism (SNP), of which there are at least 4.5 million. The challenge now becomes how to discover which polymorphisms alter cancer in humans and how to begin to understand their mechanism of action. In this report, a series of recent publications will be reviewed that have studied a polymorphism in the p53 tumor suppressor pathway, MDM2 SNP309. These reports have lent insights into how germline genetic variants of the p53 pathway could interact with gender, environmental stresses and tumor genetics to affect cancer in humans. Importantly, these observations have also exposed potential nodes of intervention, which could prove valuable in both the prevention and treatment of this disease in humans.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1

Similar content being viewed by others

References

  • Alhopuro P, Ylisaukko-Oja SK, Koskinen WJ, Bono P, Arola J, Jarvinen HJ et al. (2005). The MDM2 promoter polymorphism SNP309T → G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck. J Med Genet 42: 694–698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allazzouzi H, Suriano G, Guerra A, Plaja A, Espin E, Armengol M et al. (2006). Tumour selection advantage of non-dominant negative p53 mutations in homozygous mdm2-snp309 colorectal cancer cells. J Med Genet [Epub ahead of print].

  • Alt JR, Greiner TC, Cleveland JL, Eischen CM . (2003). Mdm2 haplo-insufficiency profoundly inhibits Myc-induced lymphomagenesis. EMBO J 22: 1442–1450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arva NC, Gopen TR, Talbott KE, Campbell LE, Chicas A, White DE et al. (2005). A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J Biol Chem 280: 26776–26787.

    Article  CAS  PubMed  Google Scholar 

  • Beckmann MW, Niederacher D, Schnurch HG, Gusterson BA, Bender HG . (1997). Multistep carcinogenesis of breast cancer and tumour heterogeneity. J Mol Med 75: 429–439.

    Article  CAS  PubMed  Google Scholar 

  • Boersma BJ, Howe TM, Goodman JE, Yfantis HG, Lee DH, Chanock SJ et al. (2006). Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst 98: 911–919.

    Article  CAS  PubMed  Google Scholar 

  • Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H et al. (2006a). MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66: 5104–5110.

    Article  CAS  PubMed  Google Scholar 

  • Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC 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: 591–602.

    Article  CAS  PubMed  Google Scholar 

  • Bond GL, Hu W, Levine A . (2005a). A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65: 5481–5484.

    Article  CAS  PubMed  Google Scholar 

  • Bond GL, Hu W, Levine AJ . (2005b). MDM2 is a central node in the p53 pathway: 12 years and counting. Curr Cancer Drug Targets 5: 3–8.

    Article  CAS  PubMed  Google Scholar 

  • Bond GL, Menin C, Bertorelle R, Alhorpuro P, Aaltonen LA, Levine AJ . (2006b). MDM2 SNP309 Accelerates colorectal tumour formation in women. J Med Genet 43: 950–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L et al. (2006). Impact of the MDM2 SNP309 and TP53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 43: 531–533.

    Article  CAS  PubMed  Google Scholar 

  • Campbell IG, Eccles DM, Choong DY . (2006). No association of the MDM2 SNP309 polymorphism with risk of breast or ovarian cancer. Cancer Lett 240: 195–197.

    Article  CAS  PubMed  Google Scholar 

  • Copson ER, White HE, Blaydes JP, Robinson DO, Johnson PW, Eccles DM . (2006). Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers. BMC Cancer 6: 80.

    Article  PubMed  PubMed Central  Google Scholar 

  • DeMarini DM . (2004). Genotoxicity of tobacco smoke and tobacco smoke condensate: a review. Mutat Res 567: 447–474.

    Article  CAS  PubMed  Google Scholar 

  • Dharel N, Kato N, Muroyama R, Moriyama M, Shao RX, Kawabe T et al. (2006). MDM2 promoter SNP309 is associated with the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Clin Cancer Res 12: 4867–4871.

    Article  CAS  PubMed  Google Scholar 

  • Elledge RM, Green S, Pugh R, Allred DC, Clark GM, Hill J et al. (2000). Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer 89: 111–117.

    Article  CAS  PubMed  Google Scholar 

  • Freedman DA, Wu L, Levine AJ . (1999). Functions of the MDM2 oncoprotein. Cell Mol Life Sci 55: 96–107.

    Article  CAS  PubMed  Google Scholar 

  • Ganguli G, Abecassis J, Wasylyk B . (2000). MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis. EMBO J 19: 5135–5147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gudas JM, Nguyen H, Klein RC, Katayose D, Seth P, Cowan KH . (1995). Differential expression of multiple MDM2 messenger RNAs and proteins in normal and tumorigenic breast epithelial cells. Clin Cancer Res 1: 71–80.

    CAS  PubMed  Google Scholar 

  • Hong Y, Miao X, Zhang X, Ding F, Luo A, Guo Y et al. (2005). The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res 65: 9582–9587.

    Article  CAS  PubMed  Google Scholar 

  • Hu Z, Ma H, Lu D, Qian J, Zhou J, Chen Y et al. (2006). Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population. Int J Cancer 118: 1275–1278.

    Article  CAS  PubMed  Google Scholar 

  • Johnson TM, Attardi LD . (2006). Dissecting p53 tumor suppressor function in vivo through the analysis of genetically modified mice. Cell Death Differ 13: 902–908.

    Article  CAS  PubMed  Google Scholar 

  • Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A . (1998). Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA 95: 15608–15612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan S, Abdelrahim M, Samudio I, Safe S . (2003). Estrogen receptor/Sp1 complexes are required for induction of cad gene expression by 17beta-estradiol in breast cancer cells. Endocrinology 144: 2325–2335.

    Article  CAS  PubMed  Google Scholar 

  • Kinyamu HK, Archer TK . (2003). Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression. Mol Cell Biol 23: 5867–5881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lane DP . (2005). Exploiting the p53 pathway for the diagnosis and therapy of human cancer. Cold Spring Harb Symp Quant Biol 70: 489–497.

    Article  CAS  PubMed  Google Scholar 

  • Levrero M . (2006). Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene 25: 3834–3847.

    Article  CAS  PubMed  Google Scholar 

  • Li G, Zhai X, Zhang Z, Chamberlain RM, Spitz MR, Wei Q . (2006). MDM2 gene promoter polymorphisms and risk of lung cancer: a case–control analysis. Carcinogenesis 27: 2028–2033.

    Article  CAS  PubMed  Google Scholar 

  • Lind H, Zienolddiny S, Ekstrom PO, Skaug V, Haugen A . (2006). Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int J Cancer 119: 718–721.

    Article  CAS  PubMed  Google Scholar 

  • Lundgren K, Montes de Oca Luna R, McNeill YB, Emerick EP, Spencer B, Barfield CR et al. (1997). Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev 11: 714–725.

    Article  CAS  PubMed  Google Scholar 

  • Ma H, Hu Z, Zhai X, Wang S, Wang X, Qin J et al. (2006). Polymorphisms in the MDM2 promoter and risk of breast cancer: a case–control analysis in a Chinese population. Cancer Lett 240: 261–267.

    Article  CAS  PubMed  Google Scholar 

  • Marchetti A, Buttitta F, Girlando S, Dalla Palma P, Pellegrini S, Fina P et al. (1995). mdm2 gene alterations and mdm2 protein expression in breast carcinomas. J Pathol 175: 31–38.

    Article  CAS  PubMed  Google Scholar 

  • Mendrysa SM, O'Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA et al. (2006). Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev 20: 16–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Menin C, Scaini MC, De Salvo GL, Biscuola M, Quaggio M, Esposito G et al. (2006). Association between MDM2-SNP309 and age at colorectal cancer diagnosis according to p53 mutation status. J Natl Cancer Inst 98: 285–288.

    Article  CAS  PubMed  Google Scholar 

  • Millikan RC, Heard K, Winkel S, Hill EJ, Heard K, Massa B et al. (2006). No association between the MDM2-309 T/G promoter polymorphism and breast cancer in African-Americans or whites. Cancer Epidemiol Biomarkers Prev 15: 175–177.

    Article  CAS  PubMed  Google Scholar 

  • Ohkubo S, Tanaka T, Taya Y, Kitazato K, Prives C . (2006). Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription. J Biol Chem 281: 16943–16950.

    Article  CAS  PubMed  Google Scholar 

  • Ohmiya N, Taguchi A, Mabuchi N, Itoh A, Hirooka Y, Niwa Y et al. (2006). MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. J Clin Oncol 24: 4434–4440.

    Article  CAS  PubMed  Google Scholar 

  • Okumura N, Saji S, Eguchi H, Nakashima S, Saji S, Hayashi S . (2002). Distinct promoter usage of mdm2 gene in human breast cancer. Oncol Rep 9: 557–563.

    CAS  PubMed  Google Scholar 

  • Olivier M, Eeles R, Hollstein M, Khan MA, Harris CC, Hainaut P . (2002). The IARC TP53 database: new online mutation analysis and recommendations to users. Hum Mutat 19: 607–614.

    Article  CAS  PubMed  Google Scholar 

  • Onel K, Cordon-Cardo C . (2004). MDM2 and prognosis. Mol Cancer Res 2: 1–8.

    CAS  PubMed  Google Scholar 

  • Osborne CK . (1998). Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 51: 227–238.

    Article  CAS  PubMed  Google Scholar 

  • Park SH, Choi JE, Kim EJ, Jang JS, Han HS, Lee WK et al. (2006). MDM2 309T>G polymorphism and risk of lung cancer in a Korean population. Lung Cancer 54: 19–24.

    Article  PubMed  Google Scholar 

  • Petz LN, Ziegler YS, Schultz JR, Kim H, Kemper JK, Nardulli AM . (2004). Differential regulation of the human progesterone receptor gene through an estrogen response element half site and Sp1 sites. J Steroid Biochem Mol Biol 88: 113–122.

    Article  CAS  PubMed  Google Scholar 

  • Pharoah PD, Day NE, Caldas C . (1999). Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. Br J Cancer 80: 1968–1973.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phelps M, Darley M, Primrose JN, Blaydes JP . (2003). p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Res 63: 2616–2623.

    CAS  PubMed  Google Scholar 

  • Pine SR, Mechanic LE, Bowman ED, Welsh JA, Chanock SC, Shields PG et al. (2006). MDM2 SNP309 and SNP354 are not associated with lung cancer risk. Cancer Epidemiol Biomarkers Prev 15: 1559–1561.

    Article  CAS  PubMed  Google Scholar 

  • Poyurovsky MV, Prives C . (2006). Unleashing the power of p53: lessons from mice and men. Genes Dev 20: 125–131.

    Article  CAS  PubMed  Google Scholar 

  • Royds JA, Iacopetta B . (2006). p53 and disease: when the guardian angel fails. Cell Death Differ 13: 1017–1026.

    Article  CAS  PubMed  Google Scholar 

  • Ruijs MW, Schmidt MK, Nevanlinna H, Tommiska J, Aittomaki K, Pruntel R et al. (2007). The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li-Fraumeni syndrome and related phenotypes. Eur J Hum Genet 15: 110–114.

    Article  CAS  PubMed  Google Scholar 

  • Sheikh MS, Shao ZM, Hussain A, Fontana JA . (1993). The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. Cancer Res 53: 3226–3228.

    CAS  PubMed  Google Scholar 

  • Sotamaa K, Liyanarachchi S, Mecklin JP, Jarvinen H, Aaltonen LA, Peltomaki P et al. (2005). p53 codon 72 and MDM2 SNP309 polymorphisms and age of colorectal cancer onset in Lynch syndrome. Clin Cancer Res 11: 6840–6844.

    Article  CAS  PubMed  Google Scholar 

  • Stoner M, Wormke M, Saville B, Samudio I, Qin C, Abdelrahim M et al. (2004). Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 23: 1052–1063.

    Article  CAS  PubMed  Google Scholar 

  • Swinney RM, Hsu SC, Hirschman BA, Chen TT, Tomlinson GE . (2005). MDM2 promoter variation and age of diagnosis of acute lymphoblastic leukemia. Leukemia 19: 1996–1998.

    Article  CAS  PubMed  Google Scholar 

  • Wilkening S, Bermejo JL, Burwinkel B, Klaes R, Bartram CR, Meindl A et al. (2006). The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer. Cancer Res 66: 646–648.

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Miao X, Guo Y, Tan W, Zhou Y, Sun T et al. (2006). Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer. Hum Mutat 27: 110–117.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Elisabeth E Bond, Suzanne Christen and Wenwei Hu for their help in preparation of the manuscript. Support of this work comes from the Breast Cancer Research Foundation, The Simons Foundation and the Leon Levy Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A J Levine.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bond, G., Levine, A. A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene 26, 1317–1323 (2007). https://doi.org/10.1038/sj.onc.1210199

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210199

Keywords

This article is cited by

Search

Quick links