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Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer

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Abstract

A single-nucleotide polymorphism (SNP) in the promoter of the Mdm2 gene (Mdm2SNP309-G) results in an increased Mdm2 expression, partial attenuation of the p53 pathway and accelerated tumor development. Clinical case–control studies indicate the Mdm2SNP309-G allele associates with a significant increase in colorectal cancer (CRC) risk that is heightened in women, but the biological significance of this polymorphism has never been directly evaluated. To examine whether the Mdm2SNP309-G allele contributes to colorectal cancer, we generated cohorts of mice harboring either the G (minor allelic variant) or T (major allelic variant) allele and treated them with azoxymethane (AOM), a carcinogen that induces sporadic colorectal cancer. Mdm2SNP309-G/G mice displayed a significant reduction in survival following AOM treatment with more colonic lesions in a wider distribution throughout the lower and upper colon and an attenuated apoptotic response following exposure. AOM did not significantly induce stabilization of wild-type p53 or activate p53 downstream targets following AOM treatment, regardless of the genotype. Instead, Mdm2SNP309-G/G colons had significant changes in the expression of genes that regulate Mdm2 transcription (ERα and Sp1) as well as downstream targets of Mdm2. Together these results suggest the Mdm2SNP309-G allele significantly impacts CRC through mechanisms outside the p53 pathway.

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References

  1. U.S. Department of Health and Human ServicesUnited States cancer statistics: 1999–2011 Cancer Incidence and Mortality Data; 1999–2011 [cited 2014; Available from: www.cdc.gov/uscs].

  2. Abdel-Fattah G, Yoffe B, Krishnan B, Khaoustov V, Itani K . MDM2/p53 protein expression in the development of colorectal adenocarcinoma. J Gastrointest Surg 2000; 4: 109–114.

    Article  CAS  Google Scholar 

  3. Mendrysa SM, McElwee MK, Michalowski J, O'Leary KA, Young KM, Perry ME . mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation. Mol Cell Biol 2003; 23: 462–472.

    Article  CAS  Google Scholar 

  4. Pant V, Xiong S, Jackson JG, Post SM, Abbas HA, Quintas-Cardama A et al. The p53-Mdm2 feedback loop protects against DNA damage by inhibiting p53 activity but is dispensable for p53 stability, development, and longevity. Genes Dev 2013; 27: 1857–1867.

    Article  CAS  Google Scholar 

  5. Post SM, Quintas-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG et al. A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 2010; 18: 220–230.

    Article  CAS  Google Scholar 

  6. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 2004; 119: 591–602.

    Article  CAS  Google Scholar 

  7. Knappskog S, Bjørnslett M, Myklebust LM, Huijts PEA, Vreeswijk MP, Edvardsen H et al. The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. Cancer Cell 2011; 19: 273–282.

    Article  CAS  Google Scholar 

  8. Bond GL, Menin C, Bertorelle R, Alhopuro P, Aaltonen LA, Levine AJ . MDM2 SNP309 accelerates colorectal tumour formation in women. J Med Genet 2006; 43: 950–952.

    Article  CAS  Google Scholar 

  9. Jin J, Wang Y, Wang J, Xu Y, Chen S, Wang J et al. Increased radiosensitivity and radiation-induced apoptosis in SRC-3 knockout mice. J Radiat Res 2014; 55: 443–450.

    Article  CAS  Google Scholar 

  10. Vogelstein B, Lane D, Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Riley MF, Lozano G . The many faces of MDM2 binding partners. Genes Cancer 2012; 3: 226–239.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Firoz EF, Warycha M, Zakrzewski J, Pollens D, Wang G, Shapiro R et al. Association of MDM2 SNP309, age of onset, and gender in cutaneous melanoma. Clin Cancer 2009; 15: 2573–2580.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Knappskog S, Trovik J, Marcickiewicz J, Tingulstad S, Staff AC, Romundstad P et al. SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer. Eur J Cancer 2012; 48: 1988–1996.

    Article  CAS  Google Scholar 

  17. Brekman A, Singh K, Polotskaia A, Kundu N, Bargonetti J . A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res 2011; 13: R3.

    Article  CAS  Google Scholar 

  18. Hu W, Feng Z, Ma L, Wagner J, Rice JJ, Stolovitzky G et al. A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res 2007; 67: 2757–2765.

    Article  CAS  Google Scholar 

  19. Robertis MD ME, Poeta ML, Carotti S, Morini S, Cecchetelli L, Signori E et al. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J Carcinog 2011; 10: 9.

    Article  Google Scholar 

  20. Hu Y, Le Leu RK, Young GP . Absence of acute apoptotic response to genotoxic carcinogens in p53-deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumours. Int J Cancer 2005; 115: 561–567.

    Article  CAS  Google Scholar 

  21. Nambiar PR, Giardina C, Guda K, Aizu W, Raja R, Rosenberg DW . Role of the alternating reading frame (P19)-p53 pathway in an in vivo murine colon tumor model. Cancer Res 2002; 62: 3667–3674.

    CAS  PubMed  Google Scholar 

  22. Heijmans J, Wielenga MCB, Rosekrans SL, van Lidth de Jeude JF, Roelofs J, Groothuis P et al. Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer. Gut 2014; 63: 310–316.

    Article  CAS  Google Scholar 

  23. Armstrong CM, Billimek AR, Allred KF, Sturino JM, Weeks BR, Allred C . A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation. Endocr-Relat Cancer 2013; 20: 515–525.

    Article  CAS  Google Scholar 

  24. Chaar I, Arfaoui TA, El Amine el HO, Mahmoud LB, Khiari M, Sammoud S et al. Impact of MDM2 polymorphism: increased risk of developing colorectal cancer and a poor prognosis in the Tunisian population. Eur J Gastroenterol Hepatol 2012; 24: 320–327.

    Article  CAS  Google Scholar 

  25. Wang W, Du M, Gu D, Zhu L, Chu H, Tong N et al. MDM2 SNP309 polymorphism is associated with colorectal cancer risk. Sci Rep 2014; 4: 4851.

    Article  CAS  Google Scholar 

  26. Bissahoyo A, Pearsall RS, Hanlon K, Amann V, Hicks D, Godfrey VL et al. Azoxymethane is a genetic background-dependent colorectal tumor initiator and promoter in mice: effects of dose, route, and diet. Toxicol Sci 2005; 88: 340–345.

    Article  CAS  Google Scholar 

  27. Ferreira K, Kreutz C, MacNelly S, Neubert K, Haber A, Bogyo M et al. Caspase-3 feeds back on caspase-8 Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. Apoptosis 2012; 17: 503–515.

    Article  CAS  Google Scholar 

  28. Lang GA, Iwakuma T, Suh Y-A, Liu G, Rao VA, Parant JM et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 2004; 119: 861–872.

    Article  CAS  Google Scholar 

  29. Poole AJ, Heap D, Carroll RE, Tyner AL . Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon. Oncogene 2004; 23: 8128–8134.

    Article  CAS  Google Scholar 

  30. Itoh Y, Hayashi H, Miyazawa K, Kojima S, Akahoshi T, Onozaki K . 17β-estradiol induces IL-1α gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor α (ERα) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ERα. J Immunol 2007; 178: 3059–3066.

    Article  CAS  Google Scholar 

  31. Hwang HC, Clurman BE . Cyclin E in normal and neoplastic cell cycles. Oncogene 2005; 24: 2776–2786.

    Article  CAS  Google Scholar 

  32. Tien JC-Y, Xu J . Steroid receptor coactivator-3 as a potential molecular target for cancer therapy. Expert Opin Ther Targets 2012; 16: 1085–1096.

    Article  CAS  Google Scholar 

  33. Fu W, Ma Q, Chen L, Li P, Zhang M, Ramamoorthy S et al. MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 2009 284. 13987–14000.

    Article  CAS  Google Scholar 

  34. Qin X, Peng Q, Tang W, Lao X, Chen Z, Lai H et al. An updated meta-analysis on the association of MDM2 SNP309 polymorphism with colorectal cancer risk. PLoS ONE 2013; 8: e76031.

    Article  CAS  Google Scholar 

  35. Greer EL, Brunet A . FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005; 24: 7410–7425.

    Article  CAS  Google Scholar 

  36. Emerling BM, Weinberg F, Liu J-L, Mak TW, Chandel NS . PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci USA 2008; 105: 2622–2627.

    Article  CAS  Google Scholar 

  37. Modur V, Nagarajan R, Evers BM, Milbrandt J . FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression: implications for PTEN mutation in prostate cancer. J Biol Chem 2002; 277: 47928–47937.

    Article  CAS  Google Scholar 

  38. Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G et al. Ligand-, cell-, and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem 2000; 275: 5379–5387.

    Article  CAS  Google Scholar 

  39. Wang F, Hoivik D, Pollenz R, Safe S . Functional and physical interactions between the estrogen receptor Sp1 and nuclear aryl hydrocarbon receptor complexes. Nucleic Acids Res 1998; 26: 3044–3052.

    Article  CAS  Google Scholar 

  40. Duong V, Boulle N, Daujat S, Chauvet J, Bonnet S, Neel H et al. Differential regulation of estrogen receptor α turnover and transactivation by Mdm2 and stress-inducing agents. Cancer Res 2007; 67: 5513–5521.

    Article  CAS  Google Scholar 

  41. Kim K, Burghardt R, Barhoumi R, Lee S-o, Liu X, Safe S . MDM2 regulates estrogen receptor α and estrogen responsiveness in breast cancer cells. J Mol Endocrinol 2011; 46: 67–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ferriere F, Habauzit D, Pakdel F, Saligaut C, Flouriot G . Unliganded estrogen receptor alpha promotes PC12 survival during serum starvation. PLoS ONE 2013; 8: e69081.

    Article  CAS  Google Scholar 

  43. Brendel A, Felzen V, Morawe T, Manthey D, Behl C . Differential regulation of apoptosis-associated genes by estrogen receptor alpha in human neuroblastoma cells. Restor Neurol Neurosci 2013; 31: 199–211.

    CAS  PubMed  Google Scholar 

  44. Barboza JA, Iwakuma T, Terzian T, El-Naggar AK, Lozano G . Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol Cancer Res 2008; 6: 947–954.

    Article  CAS  Google Scholar 

  45. Spandidos A, Wang X, Wang H, Dragnev S, Thurber T, Seed B . A comprehensive collection of experimentally validated primers for polymerase chain reaction quantitation of murine transcript abundance. BMC Genomics 2008; 9: 633.

    Article  Google Scholar 

  46. James AW, Theologis AA, Brugmann SA, Xu Y, Carre AL, Leucht P et al. Estrogen/estrogen receptor alpha signaling in mouse posterofrontal cranial suture fusion. PLoS ONE 2009; 4: e7120.

    Article  Google Scholar 

  47. Suh Y-A, Post SM, Elizondo-Fraire AC, Maccio DR, Jackson JG, El-Naggar AK et al. Multiple stress signals activate mutant p53 in vivo. Cancer Res 2011; 71: 7168–7175.

    Article  CAS  Google Scholar 

  48. Post SM, Quintas-Cardama A, Terzian T, Smith C, Eischen CM, Lozano G . p53-dependent senescence delays Emu-myc-induced B-cell lymphomagenesis. Oncogene 2010; 29: 1260–1269.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Maurisa Flynn-Croce and Brittany N Kleb for reviewing and editing the manuscript. These studies were supported by Cancer Center support grant CA016672 and funding from the Center for Genetics and Genomics and MDACC start-up funds to (SMP).

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA,

    X Zhang & S M Post

  2. Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    L Pageon

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Correspondence to S M Post.

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Zhang, X., Pageon, L. & Post, S. Impact of the Mdm2SNP309-G allele on a murine model of colorectal cancer. Oncogene 34, 4412–4420 (2015). https://doi.org/10.1038/onc.2014.377

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