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Myc, Aurora Kinase A, and mutant p53R172H co-operate in a mouse model of metastatic skin carcinoma

Oncogene volume 31, pages 2680–2690 (2012)Cite this article

Abstract

Clinical observations, as well as data obtained from the analysis of genetically engineered mouse models, firmly established the gain-of-function (GOF) properties of certain p53 mutations. However, little is known about the underlying mechanisms. We have used two independent microarray platforms to perform a comprehensive and global analysis of tumors arising in a model of metastatic skin cancer progression, which compares the consequences of a GOF p53R172H mutant vs p53 deficiency. DNA profiling revealed a higher level of genomic instability in GOF vs loss-of-function (LOF) p53 squamous cell carcinomas (SCCs). Moreover, GOF p53 SCCs showed preferential amplification of Myc with a corresponding increase in its expression and deregulation of Aurora Kinase A. Fluorescent in situ hybridization confirmed amplification of Myc in primary GOF p53 SCCs and its retention in metastatic tumors. We also identified by RNA profiling distinct gene expression profiles in GOF p53 tumors, which included enriched integrin and Rho signaling, independent of tumor stage. Thus, the progression of GOF p53 papillomas to carcinoma was marked by the acquisition of epithelial-to-mesenchymal transition and metastatic signatures. In contrast, LOF p53 tumors showed enrichment of genes associated with cancer proliferation and chromosomal instability. Collectively, these observations suggest that genomic instability has a prominent role in the early stages of GOF p53 tumor progression (that is, papillomas), whereas it is implicated at a later stage in LOF p53 tumors (that is, SCCs). This model will allow us to identify specific targets in mutant p53 SCCs, which may lead to the development of new therapeutic agents for the treatment of metastatic SCCs.

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References

  • Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E et al. (2006). The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol 55: 490–500.

    Article  Google Scholar 

  • Birkenfeld J, Nalbant P, Bohl BP, Pertz O, Hahn KM, Bokoch GM . (2007). GEF-H1 modulates localized RhoA activation during cytokinesis under the control of mitotic kinases. Dev Cell 12: 699–712.

    Article  CAS  Google Scholar 

  • Birkenfeld J, Nalbant P, Yoon SH, Bokoch GM . (2008). Cellular functions of GEF-H1, a microtubule-regulated Rho-GEF: is altered GEF-H1 activity a crucial determinant of disease pathogenesis? Trends Cell Biol 18: 210–219.

    Article  CAS  Google Scholar 

  • Boelens MC, Kok K, van der Vlies P, van der Vries G, Sietsma H, Timens W et al. (2009). Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. Lung Cancer 66: 372–378.

    Article  Google Scholar 

  • Bougeard G, Sesboue R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J et al. (2008). Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 45: 535–538.

    Article  CAS  Google Scholar 

  • Boukamp P . (2005). Non-melanoma skin cancer: what drives tumor development and progression? Carcinogenesis 26: 1657–1667.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z . (2006). A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38: 1043–1048.

    CAS  Google Scholar 

  • Caulin C, Nguyen T, Lang GA, Goepfert TM, Brinkley BR, Cai WW et al. (2007). An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 p53 mutations. J Clin Invest 117: 1893–1901.

    Article  CAS  Google Scholar 

  • Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY et al. (2010). Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 12: 457–467.

    Article  CAS  Google Scholar 

  • Cheok CF, Kua N, Kaldis P, Lane DP . (2010). Combination of nutlin-3 and VX-680 selectively targets p53 mutant cells with reversible effects on cells expressing wild-type p53. Cell Death Differ 17: 1486–1500.

    Article  CAS  Google Scholar 

  • Cheok CF, Verma CS, Baselga J, Lane DP . (2011). Translating p53 into the clinic. Nat Rev Clin Oncol 8: 25–37.

    Article  CAS  Google Scholar 

  • Cho KB, Cho MK, Lee WY, Kang KW . (2010). Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett 293: 230–239.

    Article  CAS  Google Scholar 

  • Dajee M, Lazarov M, Zhang JY, Cai T, Green CL, Russell AJ et al. (2003). NF-kappaB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421: 639–643.

    Article  CAS  Google Scholar 

  • Daya-Grosjean L, Sarasin A . (2005). The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutat Res 571: 43–56.

    Article  CAS  Google Scholar 

  • den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A et al. (2010). Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116: 1498–1505.

    Article  CAS  Google Scholar 

  • Dennis Jr G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. (2003). DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4: P3.

    Article  Google Scholar 

  • Denys H, Braems G, Lambein K, Pauwels P, Hendrix A, De Boeck A et al. (2009). The extracellular matrix regulates cancer progression and therapy response: implications for prognosis and treatment. Curr Pharm Des 15: 1373–1384.

    Article  CAS  Google Scholar 

  • Doyle B, Morton JP, Delaney DW, Ridgway RA, Wilkins JA, Sansom OJ . (2010). p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. J Pathol 222: 129–137.

    Article  CAS  Google Scholar 

  • Euvrard S, Kanitakis J, Claudy A . (2003). Skin cancers after organ transplantation. N Engl J Med 348: 1681–1691.

    Article  Google Scholar 

  • Fukasawa K . (2005). Centrosome amplification, chromosome instability and cancer development. Cancer Lett 230: 6–19.

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.

    Article  CAS  Google Scholar 

  • Harris SL, Levine AJ . (2005). The p53 pathway: positive and negative feedback loops. Oncogene 24: 2899–2908.

    Article  CAS  Google Scholar 

  • Haughey BH, von Hoff DD, Windle BE, Wahl GM, Mock PM . (1992). c-myc oncogene copy number in squamous carcinoma of the head and neck. Am J Otolaryngol 13: 168–171.

    Article  CAS  Google Scholar 

  • Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH et al. (2005). Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7: 469–483.

    Article  CAS  Google Scholar 

  • Hochberg Y, Benjamini Y . (1990). More powerful procedures for multiple significance testing. Stat Med 9: 811–818.

    Article  CAS  Google Scholar 

  • Huang da W, Sherman BT, Lempicki RA . (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44–57.

    Article  Google Scholar 

  • Jechlinger M, Grunert S, Tamir IH, Janda E, Ludemann S, Waerner T et al. (2003). Expression profiling of epithelial plasticity in tumor progression. Oncogene 22: 7155–7169.

    Article  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ . (2009). Cancer statistics, 2009. CA Cancer J Clin 59: 225–249.

    Article  Google Scholar 

  • Karlsson R, Pedersen ED, Wang Z, Brakebusch C . (2009). Rho GTPase function in tumorigenesis. Biochim Biophys Acta 1796: 91–98.

    CAS  Google Scholar 

  • Karthigeyan D, Prasad SB, Shandilya J, Agrawal S, Kundu TK . (2010). Biology of Aurora A kinase: Implications in cancer manifestation and therapy. Med Res Rev 31: 757–793.

    PubMed  Google Scholar 

  • Kemp CJ, Donehower LA, Bradley A, Balmain A . (1993). Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74: 813–822.

    Article  CAS  Google Scholar 

  • Kim YH, Girard L, Giacomini CP, Wang P, Hernandez-Boussard T, Tibshirani R et al. (2006). Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25: 130–138.

    Article  CAS  Google Scholar 

  • Kozma L, Kiss I, Szakall S, Ember I . (1994). Investigation of c-myc oncogene amplification in colorectal cancer. Cancer Lett 81: 165–169.

    Article  CAS  Google Scholar 

  • Kreimer-Erlacher H, Seidl H, Back B, Cerroni L, Kerl H, Wolf P . (2003). High frequency of ultraviolet mutations at the INK4a-ARF locus in squamous cell carcinomas from psoralen-plus-ultraviolet-A-treated psoriasis patients. J Invest Dermatol 120: 676–682.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Lee JS, Chu IS, Mikaelyan A, Calvisi DF, Heo J, Reddy JK et al. (2004). Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 36: 1306–1311.

    Article  CAS  Google Scholar 

  • Lim SK, Gopalan G . (2007). Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. Biochem J 403: 119–127.

    Article  CAS  Google Scholar 

  • Liu G, McDonnell TJ, Montes de Oca Luna R, Kapoor M, Mims B, El-Naggar AK et al. (2000). High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci U S A 97: 4174–4179.

    Article  CAS  Google Scholar 

  • Lu SL, Herrington H, Reh D, Weber S, Bornstein S, Wang D et al. (2006). Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev 20: 1331–1342.

    Article  CAS  Google Scholar 

  • Mizuarai S, Yamanaka K, Kotani H . (2006). Mutant p53 induces the GEF-H1 oncogene, a guanine nucleotide exchange factor-H1 for RhoA, resulting in accelerated cell proliferation in tumor cells. Cancer Res 66: 6319–6326.

    Article  CAS  Google Scholar 

  • Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J et al. (2003). PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34: 267–273.

    Article  CAS  Google Scholar 

  • Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S et al. (2009). Mutant p53 drives invasion by promoting integrin recycling. Cell 139: 1327–1341.

    Article  Google Scholar 

  • Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT et al. (2004). Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119: 847–860.

    Article  CAS  Google Scholar 

  • Ozakyol A, Ozdemir M, Artan S . (2006). Fish detected p53 deletion and N-MYC amplification in colorectal cancer. Hepatogastroenterology 53: 192–195.

    CAS  PubMed  Google Scholar 

  • Paterson IC, Eveson JW, Prime SS . (1996). Molecular changes in oral cancer may reflect aetiology and ethnic origin. Eur J Cancer B Oral Oncol 32B: 150–153.

    Article  CAS  Google Scholar 

  • Pierceall WE, Goldberg LH, Tainsky MA, Mukhopadhyay T, Ananthaswamy HN . (1991). Ras gene mutation and amplification in human nonmelanoma skin cancers. Mol Carcinog 4: 196–202.

    Article  CAS  Google Scholar 

  • Prochownik EV, Li Y . (2007). The ever expanding role for c-Myc in promoting genomic instability. Cell Cycle 6: 1024–1029.

    Article  CAS  Google Scholar 

  • Ramos DM, But M, Regezi J, Schmidt BL, Atakilit A, Dang D et al. (2002). Expression of integrin beta 6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biol 21: 297–307.

    Article  CAS  Google Scholar 

  • Rao CV, Yamada HY, Yao Y, Dai W . (2009). Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice. Carcinogenesis 30: 1469–1474.

    Article  CAS  Google Scholar 

  • Rounbehler RJ, Schneider-Broussard R, Conti CJ, Johnson DG . (2001). Myc lacks E2F1′s ability to suppress skin carcinogenesis. Oncogene 20: 5341–5349.

    Article  CAS  Google Scholar 

  • Saha MN, Micallef J, Qiu L, Chang H . (2010). Pharmacological activation of the p53 pathway in haematological malignancies. J Clin Pathol 63: 204–209.

    Article  CAS  Google Scholar 

  • Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C et al. (2007). A cell proliferation and chromosomal instability signature in anaplastic thyroid carcinoma. Cancer Res 67: 10148–10158.

    Article  CAS  Google Scholar 

  • Sauer L, Gitenay D, Vo C, Baron VT . (2010). Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene 29: 2628–2637.

    Article  CAS  Google Scholar 

  • Shen H, Maki CG . (2011). Pharmacologic activation of p53 by small-molecule MDM2 antagonists. Curr Pharm Des 17: 560–568.

    Article  CAS  Google Scholar 

  • Shi J, Stover JS, Whitby LR, Vogt PK, Boger DL . (2009). Small molecule inhibitors of Myc/Max dimerization and Myc-induced cell transformation. Bioorg Med Chem Lett 19: 6038–6041.

    Article  CAS  Google Scholar 

  • Spencer JM, Kahn SM, Jiang W, DeLeo VA, Weinstein IB . (1995). Activated ras genes occur in human actinic keratoses, premalignant precursors to squamous cell carcinomas. Arch Dermatol 131: 796–800.

    Article  CAS  Google Scholar 

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. (2005). Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545–15550.

    Article  CAS  Google Scholar 

  • Sun Y, Nakamura K, Wendel E, Colburn N . (1993). Progression toward tumor cell phenotype is enhanced by overexpression of a mutant p53 tumor-suppressor gene isolated from nasopharyngeal carcinoma. Proc Natl Acad Sci U S A 90: 2827–2831.

    Article  CAS  Google Scholar 

  • Sur S, Pagliarini R, Bunz F, Rago C, Diaz Jr LA, Kinzler KW et al. (2009). A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53. Proc Natl Acad Sci U S A 106: 3964–3969.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Torchia EC, Chen Y, Sheng H, Katayama H, Fitzpatrick J, Brinkley WR et al. (2009). A genetic variant of Aurora kinase A promotes genomic instability leading to highly malignant skin tumors. Cancer Res 69: 7207–7215.

    Article  CAS  Google Scholar 

  • van der Meel R, Symons MH, Kudernatsch R, Kok RJ, Schiffelers RM, Storm G et al. (2011). The VEGF/Rho GTPase signalling pathway: A promising target for anti-angiogenic/anti-invasion therapy. Drug Discov Today 16: 219–228.

    Article  CAS  Google Scholar 

  • Wang XJ, Greenhalgh DA, Jiang A, He D, Zhong L, Brinkley BR et al. (1998). Analysis of centrosome abnormalities and angiogenesis in epidermal-targeted p53172H mutant and p53-knockout mice after chemical carcinogenesis: evidence for a gain of function. Mol Carcinog 23: 185–192.

    Article  CAS  Google Scholar 

  • Wolf P, Kreimer-Erlacher H, Seidl H, Back B, Soyer HP, Kerl H . (2004). The ultraviolet fingerprint dominates the mutational spectrum of the p53 and Ha-ras genes in psoralen + ultraviolet A keratoses from psoriasis patients. J Invest Dermatol 122: 190–200.

    Article  CAS  Google Scholar 

  • Xu L, Shen SS, Hoshida Y, Subramanian A, Ross K, Brunet JP et al. (2008). Gene expression changes in an animal melanoma model correlate with aggressiveness of human melanoma metastases. Mol Cancer Res 6: 760–769.

    Article  CAS  Google Scholar 

  • Yakut T, Egeli U, Gebitekin C . (2003). Investigation of c-myc and p53 gene alterations in the tumor and surgical borderline tissues of NSCLC and effects on clinicopathologic behavior: by the FISH technique. Lung 181: 245–258.

    Article  CAS  Google Scholar 

  • Yang S, He S, Zhou X, Liu M, Zhu H, Wang Y et al. (2010). Suppression of Aurora-A oncogenic potential by c-Myc downregulation. Exp Mol Med 42: 759–767.

    Article  CAS  Google Scholar 

  • Yu X, Minter-Dykhouse K, Malureanu L, Zhao WM, Zhang D, Merkle CJ et al. (2005). Chfr is required for tumor suppression and Aurora A regulation. Nat Genet 37: 401–406.

    Article  CAS  Google Scholar 

  • Zhang B, Schmoyer D, Kirov S, Snoddy J . (2004). GOTree Machine (GOTM): a web-based platform for interpreting sets of interesting genes using Gene Ontology hierarchies. BMC Bioinformatics 5: 16.

    Article  Google Scholar 

  • Zheng S, El-Naggar AK, Kim ES, Kurie JM, Lozano G . (2007). A genetic mouse model for metastatic lung cancer with gender differences in survival. Oncogene 26: 6896–6904.

    Article  CAS  Google Scholar 

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Acknowledgements

Grant Support: NIH grants: DE015344 (CC), CA52607 and CA105491 (DRR). We acknowledge Dr Lisa White and Laura Liles for their assistance with microarray experiments; Dr Leila Garcia for her assistance with the FISH experiments and Dr Ariefdjohan for the reading of the manuscript. This work was funded by grants from the National Institute of Cancer, USA.

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  1. E C Torchia and C Caulin: These authors contributed equally to this work.

Authors and Affiliations

  1. Departmant of Dermatology and Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    E C Torchia, T Terzian, B J Kubick, N F Box & D R Roop

  2. Departmant of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    C Caulin & S Acin

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  1. E C Torchia
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Torchia, E., Caulin, C., Acin, S. et al. Myc, Aurora Kinase A, and mutant p53R172H co-operate in a mouse model of metastatic skin carcinoma. Oncogene 31, 2680–2690 (2012). https://doi.org/10.1038/onc.2011.441

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