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Wip1 phosphatase in breast cancer

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Abstract

Understanding the factors contributing to tumor initiation, progression and evolution is of paramount significance. Among them, wild-type p53-induced phosphatase 1 (Wip1) is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways. Originally discovered as a p53-regulated gene, Wip1 has been subsequently found amplified and more recently mutated in a significant fraction of human cancers including breast tumors. Recent development in the field further uncovered the utility of anti-Wip1-directed therapies in delaying tumor onset or in reducing the tumor burden. Furthermore, Wip1 could be an important factor that contributes to tumor heterogeneity, suggesting that its inhibition may decrease the rate of cancer evolution. These effects depend on several signaling pathways modulated by Wip1 phosphatase in a spatial and temporal manner. In this review we discuss the recent development in understanding how Wip1 contributes to tumorigenesis with its relevance to breast cancer.

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References

  1. Harper JW, Elledge SJ . The DNA damage response: ten years after. Mol Cell 2007; 28: 739–745.

    CAS  PubMed  Google Scholar 

  2. Lord CJ, Ashworth A . The DNA damage response and cancer therapy. Nature 2012; 481: 287–294.

    CAS  Google Scholar 

  3. Bouwman P, Jonkers J . The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 2012; 12: 587–598.

    CAS  PubMed  Google Scholar 

  4. Curtin NJ . DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012; 12: 801–817.

    CAS  Google Scholar 

  5. Lønning PE, Knappskog S . Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers. Oncogene 2013; 32: 5315–5330.

    PubMed  Google Scholar 

  6. Polo SE, Jackson SP . Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev 2011; 25: 409–433.

    Article  CAS  Google Scholar 

  7. Shimada M, Nakanishi M . Response to DNA damage: why do we need to focus on protein phosphatases? Front Oncol 2013; 3: 8.

    CAS  PubMed  Google Scholar 

  8. Jackson SP, Durocher D . Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 2013; 49: 795–807.

    CAS  PubMed  Google Scholar 

  9. Ulrich HD . Ubiquitin and SUMO in DNA repair at a glance. J Cell Sci 2012; 125: 249–254.

    CAS  PubMed  Google Scholar 

  10. Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE et al. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Natl Acad Sci USA 1997; 94: 6048–6053.

    CAS  PubMed  Google Scholar 

  11. Shreeram S, Demidov ON, Hee WK, Yamaguchi H, Onishi N, Kek C et al. Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol Cell 2006; 23: 757–764.

    CAS  PubMed  Google Scholar 

  12. Lu X, Nannenga B, Donehower LA . PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Genes Dev 2005; 19: 1162–1174.

    CAS  PubMed  Google Scholar 

  13. Fujimoto H, Onishi N, Kato N, Takekawa M, Xu XZ, Kosugi A et al. Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. Cell Death Differ 2006; 13: 1170–1180.

    CAS  Google Scholar 

  14. Yoda A, Xu XZ, Onishi N, Toyoshima K, Fujimoto H, Kato N et al. Intrinsic kinase activity and SQ/TQ domain of Chk2 kinase as well as N-terminal domain of Wip1 phosphatase are required for regulation of Chk2 by Wip1. J Biol Chem 2006; 281: 24847–24862.

    CAS  PubMed  Google Scholar 

  15. Lu X, Ma O, Nguyen T-A, Jones SN, Oren M, Donehower LA . The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 2007; 12: 342–354.

    CAS  Google Scholar 

  16. Zhang X, Lin L, Guo H, Yang J, Jones SN, Jochemsen A et al. Phosphorylation and degradation of MdmX is inhibited by Wip1 phosphatase in the DNA damage response. Cancer Res 2009; 69: 7960–7968.

    CAS  PubMed  Google Scholar 

  17. Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H et al. p53-inducible Wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. EMBO J 2000; 19: 6517–6526.

    CAS  PubMed  Google Scholar 

  18. Shaltiel IA, Aprelia M, Saurin AT, Chowdhury D, Kops GJPL, Voest EE et al. Distinct phosphatases antagonize the p53 response in different phases of the cell cycle. Proc Natl Acad Sci USA 2014; 111: 7313–7318.

    CAS  PubMed  Google Scholar 

  19. Oliva-Trastoy M, Berthonaud V, Chevalier A, Ducrot C, Marsolier-Kergoat MC, Mann C et al. The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase. Oncogene 2007; 26: 1449–1458.

    CAS  Google Scholar 

  20. Cha H, Lowe JM, Li H, Lee J-S, Belova GI, Bulavin D V et al. Wip1 directly dephosphorylates gamma-H2AX and attenuates the DNA damage response. Cancer Res 2010; 70: 4112–4122.

    CAS  PubMed  Google Scholar 

  21. Moon S-H, Lin L, Zhang X, Nguyen T-A, Darlington Y, Waldman AS et al. Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol Chem 2010; 285: 12935–12947.

    CAS  PubMed  Google Scholar 

  22. Nguyen T-A, Slattery SD, Moon S-H, Darlington YF, Lu X, Donehower LA . The oncogenic phosphatase Wip1 negatively regulates nucleotide excision repair. DNA Repair (Amst) 2010; 9: 813–823.

    CAS  PubMed  Google Scholar 

  23. Lu X, Bocangel D, Nannenga B, Yamaguchi H, Appella E, Donehower LA . The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. Mol Cell 2004; 15: 621–634.

    CAS  PubMed  Google Scholar 

  24. Macůrek L, Lindqvist A, Voets O, Kool J, Vos HR, Medema RH . Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition. Oncogene 2010; 29: 2281–2291.

    PubMed  Google Scholar 

  25. Bulavin D V, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet 2004; 36: 343–350.

    CAS  PubMed  Google Scholar 

  26. Yu E, Ahn YS, Jang SJ, Kim M-J, Yoon HS, Gong G et al. Overexpression of the Wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. Breast Cancer Res Treat 2007; 101: 269–278.

    CAS  PubMed  Google Scholar 

  27. Lowe JM, Cha H, Yang Q, Fornace AJ . Nuclear factor-kappaB (NF-kappaB) is a novel positive transcriptional regulator of the oncogenic Wip1 phosphatase. J Biol Chem 2010; 285: 5249–5257.

    CAS  Google Scholar 

  28. Chew J, Biswas S, Shreeram S, Humaidi M, Wong ET, Dhillion MK et al. Wip1 phosphatase is a negative regulator of NF-kappaB signalling. Nat Cell Biol 2009; 11: 659–666.

    CAS  PubMed  Google Scholar 

  29. Filipponi D, Muller J, Emelyanov A, Bulavin D V . Wip1 controls global heterochromatin silencing via ATM/BRCA1-dependent DNA methylation. Cancer Cell 2013; 24: 528–541.

    CAS  PubMed  Google Scholar 

  30. Bulavin D V, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA et al. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet 2002; 31: 210–215.

    CAS  Google Scholar 

  31. Sinclair CS, Rowley M, Naderi A, Couch FJ . The 17q23 amplicon and breast cancer. Breast Cancer Res Treat 2003; 78: 313–322.

    CAS  Google Scholar 

  32. Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven WG, Nguyen KC et al. Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. Nat Genet 2002; 31: 133–134.

    CAS  Google Scholar 

  33. Lambros MB, Natrajan R, Geyer FC, Lopez-Garcia MA, Dedes KJ, Savage K et al. PPM1D gene amplification and overexpression in breast cancer: a qRT-PCR and chromogenic in situ hybridization study. Mod Pathol 2010; 23: 1334–1345.

    CAS  PubMed  Google Scholar 

  34. Rauta J, Alarmo E-L, Kauraniemi P, Karhu R, Kuukasjärvi T, Kallioniemi A . The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. Breast Cancer Res Treat 2006; 95: 257–263.

    CAS  PubMed  Google Scholar 

  35. Hirasawa A, Saito-Ohara F, Inoue J, Aoki D, Susumu N, Yokoyama T et al. Association of 17q21-q24 gain in ovarian clear cell adenocarcinomas with poor prognosis and identification of PPM1D and APPBP2 as likely amplification targets. Clin Cancer Res 2003; 9: 1995–2004.

    CAS  PubMed  Google Scholar 

  36. Tan DSP, Lambros MBK, Rayter S, Natrajan R, Vatcheva R, Gao Q et al. PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin Cancer Res 2009; 15: 2269–2280.

    CAS  Google Scholar 

  37. Mendrzyk F, Radlwimmer B, Joos S, Kokocinski F, Benner A, Stange DE et al. Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. J Clin Oncol 2005; 23: 8853–8862.

    CAS  PubMed  Google Scholar 

  38. Ehrbrecht A, Muller U, Wolter M, Hoischen A, Koch A, Radlwimmer B et al. Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J Pathol 2006; 208: 554–563.

    CAS  PubMed  Google Scholar 

  39. Castellino RC, De Bortoli M, Lu X, Moon S-H, Nguyen T-A, Shepard MA et al. Medulloblastomas overexpress the p53-inactivating oncogene Wip1/PPM1D. J Neurooncol 2008; 86: 245–256.

    CAS  Google Scholar 

  40. Buss MC, Remke M, Lee J, Gandhi K, Schniederjan MJ, Kool M et al. The Wip1 oncogene promotes progression and invasion of aggressive medulloblastoma variants. Oncogene 2014. doi:10.1038/onc.2014.37.

    PubMed  Google Scholar 

  41. Loukopoulos P, Shibata T, Katoh H, Kokubu A, Sakamoto M, Yamazaki K et al. Genome-wide array-based comparative genomic hybridization analysis of pancreatic adenocarcinoma: identification of genetic indicators that predict patient outcome. Cancer Sci 2007; 98: 392–400.

    CAS  Google Scholar 

  42. Hu W, Feng Z, Modica I, Klimstra DS, Song L, Allen PJ et al. Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway. Genes Cancer 2010; 1: 360–368.

    CAS  PubMed  Google Scholar 

  43. Fuku T, Semba S, Yutori H, Yokozaki H . Increased wild-type p53-induced phosphatase 1 (Wip1 or PPM1D) expression correlated with downregulation of checkpoint kinase 2 in human gastric carcinoma. Pathol Int 2007; 57: 566–571.

    CAS  PubMed  Google Scholar 

  44. Saito-Ohara F, Imoto I, Inoue J, Hosoi H, Nakagawara A, Sugimoto T et al. PPM1D is a potential target for 17q gain in neuroblastoma. Cancer Res 2003; 63: 1876–1883.

    CAS  PubMed  Google Scholar 

  45. Jiao L, Shen D, Liu G, Jia J, Geng J, Wang H et al. PPM1D as a novel biomarker for prostate cancer after radical prostatectomy. Anticancer Res 2014; 34: 2919–2925.

    CAS  PubMed  Google Scholar 

  46. Yang D, Zhang H, Hu X, Xin S, Duan Z . Abnormality of pl6/p38MAPK/p53/Wipl pathway in papillary thyroid cancer. Gland Surg 2012; 1: 33–38.

    PubMed  Google Scholar 

  47. Peng T-S, He Y-H, Nie T, Hu X-D, Lu H-Y, Yi J et al. PPM1D is a prognostic marker and therapeutic target in colorectal cancer. Exp Ther Med 2014; 8: 430–434.

    CAS  PubMed  Google Scholar 

  48. Li G-B, Zhang X-L, Yuan L, Jiao Q-Q, Liu D-J, Liu J . Protein phosphatase magnesium-dependent 1δ (PPM1D) mRNA expression is a prognosis marker for hepatocellular carcinoma. PLoS ONE 2013; 8: e60775.

    CAS  PubMed  Google Scholar 

  49. Ma D, Zhang C-J, Chen Z-L, Yang H . Prognostic value of PPM1D in 800 gastric cancer patients. Mol Med Rep 2014; 10: 191–194.

    CAS  PubMed  Google Scholar 

  50. Kasahara K, Taguchi T, Yamasaki I, Kamada M, Yuri K, Shuin T . Detection of genetic alterations in advanced prostate cancer by comparative genomic hybridization. Cancer Genet Cytogenet 2002; 137: 59–63.

    CAS  PubMed  Google Scholar 

  51. Koo SH, Kwon KC, Ihm CH, Jeon YM, Park JW, Sul CK . Detection of genetic alterations in bladder tumors by comparative genomic hybridization and cytogenetic analysis. Cancer Genet Cytogenet 1999; 110: 87–93.

    CAS  PubMed  Google Scholar 

  52. Kleiblova P, Shaltiel IA, Benada J, Ševčík J, Pecháčková S, Pohlreich P et al. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint. J Cell Biol 2013; 201: 511–521.

    CAS  PubMed  Google Scholar 

  53. Dudgeon C, Shreeram S, Tanoue K, Mazur SJ, Sayadi A, Robinson RC et al. Genetic variants and mutations of PPM1D control the response to DNA damage. Cell Cycle 2013; 12: 2656–2664.

    CAS  PubMed  Google Scholar 

  54. Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 2013; 493: 406–410.

    CAS  PubMed  Google Scholar 

  55. Zhang L, Chen LH, Wan H, Yang R, Wang Z, Feng J et al. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 2014; 46: 726–730.

    CAS  PubMed  Google Scholar 

  56. Gilmartin AG, Faitg TH, Richter M, Groy A, Seefeld M a, Darcy MG et al. Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat Chem Biol 2014; 10: 181–187.

    CAS  PubMed  Google Scholar 

  57. Clarke RB, Howell A, Potten CS, Anderson E . Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res 1997; 57: 4987–4991.

    CAS  Google Scholar 

  58. Rosen JM . Hormone receptor patterning plays a critical role in normal lobuloalveolar development and breast cancer progression. Breast Dis 2003; 18: 3–9.

    CAS  PubMed  Google Scholar 

  59. Russo J, Russo IH . Development of the human breast. Maturitas 2004; 49: 2–15.

    CAS  Google Scholar 

  60. Miyoshi K, Shillingford JM, Smith GH, Grimm SL, Wagner KU, Oka T et al. Signal transducer and activator of transcription (Stat) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J Cell Biol 2001; 155: 531–542.

    CAS  PubMed  Google Scholar 

  61. Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L . Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997; 11: 179–186.

    CAS  PubMed  Google Scholar 

  62. Wagner K-U, Krempler A, Triplett AA, Qi Y, George NM, Zhu J et al. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol 2004; 24: 5510–5520.

    CAS  PubMed  Google Scholar 

  63. Visvader JE . Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev 2009; 23: 2563–2577.

    CAS  PubMed  Google Scholar 

  64. Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL et al. Progesterone induces adult mammary stem cell expansion. Nature 2010; 465: 803–807.

    CAS  PubMed  Google Scholar 

  65. Axlund SD, Sartorius CA . Progesterone regulation of stem and progenitor cells in normal and malignant breast. Mol Cell Endocrinol 2012; 357: 71–79.

    CAS  PubMed  Google Scholar 

  66. Horseman ND, Gregerson KA . Prolactin actions. J Mol Endocrinol 2014; 52: R95–106.

    CAS  PubMed  Google Scholar 

  67. Tarulli GA, De Silva D, Ho V, Kunasegaran K, Ghosh K, Tan BC et al. Hormone-sensing cells require Wip1 for paracrine stimulation in normal and premalignant mammary epithelium. Breast Cancer Res 2013; 15: R10.

    CAS  PubMed  Google Scholar 

  68. Polyak K . Heterogeneity in breast cancer. J Clin Invest 2011; 121: 3786–3788.

    CAS  PubMed  Google Scholar 

  69. Dawson S-J, Rueda OM, Aparicio S, Caldas C . A new genome-driven integrated classification of breast cancer and its implications. EMBO J 2013; 32: 617–628.

    CAS  PubMed  Google Scholar 

  70. Guedj M, Marisa L, de Reynies A, Orsetti B, Schiappa R, Bibeau F et al. A refined molecular taxonomy of breast cancer. Oncogene 2012; 31: 1196–1206.

    CAS  PubMed  Google Scholar 

  71. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J et al. Tumour evolution inferred by single-cell sequencing. Nature 2011; 472: 90–94.

    CAS  PubMed  Google Scholar 

  72. Kallioniemi A, Kallioniemi OP, Piper J, Tanner M, Stokke T, Chen L et al. Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc Natl Acad Sci USA 1994; 91: 2156–2160.

    CAS  PubMed  Google Scholar 

  73. Courjal F, Theillet C . Comparative genomic hybridization analysis of breast tumors with predetermined profiles of DNA amplification. Cancer Res 1997; 57: 4368–4377.

    CAS  Google Scholar 

  74. Roylance R, Gorman P, Harris W, Liebmann R, Barnes D, Hanby A et al. Comparative genomic hybridization of breast tumors stratified by histological grade reveals new insights into the biological progression of breast cancer. Cancer Res 1999; 59: 1433–1436.

    CAS  PubMed  Google Scholar 

  75. Andersen CL, Monni O, Wagner U, Kononen J, Bärlund M, Bucher C et al. High-throughput copy number analysis of 17q23 in 3520 tissue specimens by fluorescence in situ hybridization to tissue microarrays. Am J Pathol 2002; 161: 73–79.

    CAS  PubMed  Google Scholar 

  76. Moore E, Magee H, Coyne J, Gorey T, Dervan PA . Widespread chromosomal abnormalities in high-grade ductal carcinoma in situ of the breast. Comparative genomic hybridization study of pure high-grade DCIS. J Pathol 1999; 187: 403–409.

    CAS  PubMed  Google Scholar 

  77. Rennstam K, Ahlstedt-Soini M, Baldetorp B, Bendahl P-O, Borg A, Karhu R et al. Patterns of chromosomal imbalances defines subgroups of breast cancer with distinct clinical features and prognosis. A study of 305 tumors by comparative genomic hybridization. Cancer Res 2003; 63: 8861–8868.

    CAS  PubMed  Google Scholar 

  78. Bärlund M, Monni O, Kononen J, Cornelison R, Torhorst J, Sauter G et al. Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. Cancer Res 2000; 60: 5340–5344.

    PubMed  Google Scholar 

  79. Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M et al. Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. Proc Natl Acad Sci USA 2001; 98: 5711–5716.

    CAS  PubMed  Google Scholar 

  80. Kelemen LE, Wang X, Fredericksen ZS, Pankratz VS, Pharoah PDP, Ahmed S et al. Genetic variation in the chromosome 17q23 amplicon and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2009; 18: 1864–1868.

    CAS  PubMed  Google Scholar 

  81. Pärssinen J, Kuukasjärvi T, Karhu R, Kallioniemi A . High-level amplification at 17q23 leads to coordinated overexpression of multiple adjacent genes in breast cancer. Br J Cancer 2007; 96: 1258–1264.

    PubMed  Google Scholar 

  82. Vogel C, Abreu R de S, Ko D, Le S-Y, Shapiro BA, Burns SC et al. Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line. Mol Syst Biol 2010; 6: 400.

    PubMed  Google Scholar 

  83. Vogel C, Marcotte EM . Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 2012; 13: 227–232.

    CAS  PubMed  Google Scholar 

  84. Hicks J, Krasnitz A, Lakshmi B, Navin NE, Riggs M, Leibu E et al. Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res 2006; 16: 1465–1479.

    CAS  PubMed  Google Scholar 

  85. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990; 8: 103–112.

    CAS  Google Scholar 

  86. Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 1998; 16: 1340–1349.

    CAS  PubMed  Google Scholar 

  87. Carr JA, Havstad S, Zarbo RJ, Divine G, Mackowiak P, Velanovich V . The association of HER-2/neu amplification with breast cancer recurrence. Arch Surg 2000; 135: 1469–1474.

    CAS  PubMed  Google Scholar 

  88. Hyman E, Kauraniemi P, Hautaniemi S, Wolf M, Mousses S, Rozenblum E et al. Impact of DNA amplification on gene expression patterns in breast cancer. Cancer Res 2002; 62: 6240–6245.

    CAS  PubMed  Google Scholar 

  89. Orsetti B, Nugoli M, Cervera N, Lasorsa L, Chuchana P, Ursule L et al. Genomic and expression profiling of chromosome 17 in breast cancer reveals complex patterns of alterations and novel candidate genes. Cancer Res 2004; 64: 6453–6460.

    CAS  PubMed  Google Scholar 

  90. Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H et al. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 2004; 64: 8534–8540.

    CAS  PubMed  Google Scholar 

  91. Lamy P-J, Fina F, Bascoul-Mollevi C, Laberenne A-C, Martin P-M, Ouafik L et al. Quantification and clinical relevance of gene amplification at chromosome 17q12-q21 in human epidermal growth factor receptor 2-amplified breast cancers. Breast Cancer Res 2011; 13: R15.

    CAS  PubMed  Google Scholar 

  92. Letessier A, Sircoulomb F, Ginestier C, Cervera N, Monville F, Gelsi-Boyer V et al. Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers. BMC Cancer 2006; 6: 245.

    PubMed  Google Scholar 

  93. Melchor L, Alvarez S, Honrado E, Palacios J, Barroso A, Díez O et al. The accumulation of specific amplifications characterizes two different genomic pathways of evolution of familial breast tumors. Clin Cancer Res 2005; 11: 8577–8584.

    CAS  PubMed  Google Scholar 

  94. Bilal E, Vassallo K, Toppmeyer D, Barnard N, Rye IH, Almendro V et al. Amplified loci on chromosomes 8 and 17 predict early relapse in ER-positive breast cancers. PLoS ONE 2012; 7: e38575.

    CAS  PubMed  Google Scholar 

  95. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

    CAS  PubMed  Google Scholar 

  96. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98: 10869–10874.

    Google Scholar 

  97. Parker JS, Mullins M, Cheang MCU, Leung S, Voduc D, Vickery T et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009; 27: 1160–1167.

    PubMed  Google Scholar 

  98. Bergamaschi A, Kim YH, Wang P, Sørlie T, Hernandez-Boussard T, Lonning PE et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 2006; 45: 1033–1040.

    CAS  PubMed  Google Scholar 

  99. Natrajan R, Weigelt B, Mackay A, Geyer FC, Grigoriadis A, Tan DSP et al. An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers. Breast Cancer Res Treat 2010; 121: 575–589.

    CAS  PubMed  Google Scholar 

  100. Horlings HM, Lai C, Nuyten DSA, Halfwerk H, Kristel P, van Beers E et al. Integration of DNA copy number alterations and prognostic gene expression signatures in breast cancer patients. Clin Cancer Res 2010; 16: 651–663.

    CAS  PubMed  Google Scholar 

  101. Asselin-Labat M-L, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 2007; 9: 201–209.

    CAS  PubMed  Google Scholar 

  102. Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 2008; 13: 141–152.

    CAS  PubMed  Google Scholar 

  103. Henry MD, Triplett AA, Oh KB, Smith GH, Wagner K-U . Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice. Oncogene 2004; 23: 6980–6985.

    CAS  PubMed  Google Scholar 

  104. Jeselsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C et al. Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell 2010; 17: 65–76.

    CAS  PubMed  Google Scholar 

  105. Yu Q, Geng Y, Sicinski P . Specific protection against breast cancers by cyclin D1 ablation. Nature 2001; 411: 1017–1021.

    CAS  PubMed  Google Scholar 

  106. Demidov ON, Kek C, Shreeram S, Timofeev O, Fornace AJ, Appella E et al. The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene 2007; 26: 2502–2506.

    CAS  Google Scholar 

  107. Reynolds PA, Sigaroudinia M, Zardo G, Wilson MB, Benton GM, Miller CJ et al. Tumor suppressor p16INK4A regulates polycomb-mediated DNA hypermethylation in human mammary epithelial cells. J Biol Chem 2006; 281: 24790–24802.

    CAS  Google Scholar 

  108. Roy S, Gascard P, Dumont N, Zhao J, Pan D, Petrie S et al. Rare somatic cells from human breast tissue exhibit extensive lineage plasticity. Proc Natl Acad Sci USA 2013; 110: 4598–4603.

    CAS  PubMed  Google Scholar 

  109. Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin D V . Phosphatase Wip1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest 2014; 124: 3263–3273.

    CAS  PubMed  Google Scholar 

  110. Hayes MJ, Thomas D, Emmons A, Giordano TJ, Kleer CG . Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res 2008; 14: 4038–4044.

    CAS  PubMed  Google Scholar 

  111. Abraham SC, Reynolds C, Lee J-H, Montgomery EA, Baisden BL, Krasinskas AM et al. Fibromatosis of the breast and mutations involving the APC/β-catenin pathway. Hum Pathol 2002; 33: 39–46.

    CAS  PubMed  Google Scholar 

  112. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 2011; 121: 2750–2767.

    CAS  PubMed  Google Scholar 

  113. Geyer FC, Lacroix-Triki M, Savage K, Arnedos M, Lambros MB, MacKay A et al. β-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation. Mod Pathol 2011; 24: 209–231.

    CAS  Google Scholar 

  114. Li Y, Hively WP, Varmus HE . Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000; 19: 1002–1009.

    CAS  PubMed  Google Scholar 

  115. Vaillant F, Asselin-Labat M-L, Shackleton M, Forrest NC, Lindeman GJ, Visvader JE . The mammary progenitor marker CD61/beta3 integrin identifies cancer stem cells in mouse models of mammary tumorigenesis. Cancer Res 2008; 68: 7711–7717.

    CAS  PubMed  Google Scholar 

  116. Cleary AS, Leonard TL, Gestl SA, Gunther EJ . Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 2014; 508: 113–117.

    CAS  PubMed  Google Scholar 

  117. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L et al. Generation of a functional mammary gland from a single stem cell. Nature 2006; 439: 84–88.

    CAS  PubMed  Google Scholar 

  118. Li Y, Welm B, Podsypanina K, Huang S, Chamorro M, Zhang X et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc Natl Acad Sci USA 2003; 100: 15853–15858.

    CAS  Google Scholar 

  119. Liu BY, McDermott SP, Khwaja SS, Alexander CM . The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc Natl Acad Sci USA 2004; 101: 4158–4163.

    CAS  PubMed  Google Scholar 

  120. Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA 2007; 104: 12111–12116.

    CAS  PubMed  Google Scholar 

  121. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L et al. 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 2002; 20: 2310–2318.

    CAS  PubMed  Google Scholar 

  122. Foulkes WD . Germline BRCA1 Mutations and a Basal Epithelial Phenotype in Breast Cancer. J Natl Cancer Inst 2003; 95: 1482–1485.

    CAS  PubMed  Google Scholar 

  123. Ludwig T, Fisher P, Murty V, Efstratiadis A . Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene 2001; 20: 3937–3948.

    CAS  PubMed  Google Scholar 

  124. Cheung AMY, Elia A, Tsao M-S, Done S, Wagner K-U, Hennighausen L et al. Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/−) mutant mice. Cancer Res 2004; 64: 1959–1965.

    CAS  PubMed  Google Scholar 

  125. Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 2001; 29: 418–425.

    CAS  PubMed  Google Scholar 

  126. Ho GH, Calvano JE, Bisogna M, Abouezzi Z, Borgen PI, Cordón-Cardó C et al. Genetic alterations of the p14ARF -hdm2-p53 regulatory pathway in breast carcinoma. Breast Cancer Res Treat 2001; 65: 225–232.

    CAS  PubMed  Google Scholar 

  127. Momand J, Jung D, Wilczynski S, Niland J . The MDM2 gene amplification database. Nucleic Acids Res 1998; 26: 3453–3459.

    CAS  PubMed  Google Scholar 

  128. Yu Q, Li Y, Mu K, Li Z, Meng Q, Wu X et al. Amplification of Mdmx and overexpression of MDM2 contribute to mammary carcinogenesis by substituting for p53 mutations. Diagn Pathol 2014; 9: 71.

    PubMed  Google Scholar 

  129. Silwal-Pandit L, Vollan HKM, Chin S-F, Rueda OM, McKinney S, Osako T et al. p53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 2014; 20: 3569–3580.

    CAS  PubMed  Google Scholar 

  130. Mizuno H, Spike BT, Wahl GM, Levine AJ . Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures. Proc Natl Acad Sci USA 2010; 107: 22745–22750.

    CAS  PubMed  Google Scholar 

  131. Spike BT, Wahl GM . p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome. Genes Cancer 2011; 2: 404–419.

    CAS  PubMed  Google Scholar 

  132. Yagi H, Chuman Y, Kozakai Y, Imagawa T, Takahashi Y, Yoshimura F et al. A small molecule inhibitor of p53-inducible protein phosphatase PPM1D. Bioorg Med Chem Lett 2012; 22: 729–732.

    CAS  PubMed  Google Scholar 

  133. Ali AY, Abedini MR, Tsang BK . The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation. Oncogene 2012; 31: 2175–2186.

    CAS  PubMed  Google Scholar 

  134. Kong W, Jiang X, Mercer WE . Downregulation of Wip-1 phosphatase expression in MCF-7 breast cancer cells enhances doxorubicin-induced apoptosis through p53-mediated transcriptional activation of Bax. Cancer Biol Ther 2009; 8: 555–563.

    CAS  PubMed  Google Scholar 

  135. Goloudina AR, Tanoue K, Hammann A, Fourmaux E, Le Guezennec X, Bulavin D V et al. Wip1 promotes RUNX2-dependent apoptosis in p53-negative tumors and protects normal tissues during treatment with anticancer agents. Proc Natl Acad Sci USA 2012; 109: E68–E75.

    CAS  PubMed  Google Scholar 

  136. Pärssinen J, Alarmo E-L, Karhu R, Kallioniemi A . PPM1D silencing by RNA interference inhibits proliferation and induces apoptosis in breast cancer cell lines with wild-type p53. Cancer Genet Cytogenet 2008; 182: 33–39.

    Google Scholar 

  137. Torti D, Trusolino L . Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 2011; 3: 623–636.

    CAS  PubMed  Google Scholar 

  138. Goloudina AR, Mazur SJ, Appella E, Garrido C, Demidov ON . Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xL ratio. Cell Cycle 2012; 11: 1883–1887.

    CAS  PubMed  Google Scholar 

  139. Kruse JP, Gu W . Modes of p53 Regulation. Cell 2009; 137: 609–622.

    CAS  PubMed  Google Scholar 

  140. Feifei N, Mingzhi Z, Yanyun Z, Huanle Z, Fang R, Mingzhu H et al. MicroRNA expression analysis of mammospheres cultured from human breast cancers. J Cancer Res Clin Oncol 2012; 138: 1937–1944.

    PubMed  Google Scholar 

  141. Zhang X, Wan G, Mlotshwa S, Vance V, Berger FG, Chen H et al. Oncogenic Wip1 phosphatase is inhibited by miR-16 in the DNA damage signaling pathway. Cancer Res 2010; 70: 7176–7186.

    CAS  PubMed  Google Scholar 

  142. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K et al. Mutational processes molding the genomes of 21 breast cancers. Cell 2012; 149: 979–993.

    CAS  PubMed  Google Scholar 

  143. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415–421.

    CAS  PubMed  Google Scholar 

  144. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27–40.

    CAS  PubMed  Google Scholar 

  145. Smith HC, Bennett RP, Kizilyer A, McDougall WM, Prohaska KM . Functions and regulation of the APOBEC family of proteins. Semin Cell Dev Biol 2012; 23: 258–268.

    CAS  PubMed  Google Scholar 

  146. Bransteitter R, Prochnow C, Chen XS . The current structural and functional understanding of APOBEC deaminases. Cell Mol Life Sci 2009; 66: 3137–3147.

    CAS  PubMed  Google Scholar 

  147. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 2013; 494: 366–370.

    CAS  PubMed  Google Scholar 

  148. Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, Difilippantonio S et al. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 2008; 135: 1028–1038.

    CAS  PubMed  Google Scholar 

  149. Kazazian HH, Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE . Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 1988; 332: 164–166.

    CAS  PubMed  Google Scholar 

  150. Hancks DC, Kazazian HH . Active human retrotransposons: variation and disease. Curr Opin Genet Dev 2012; 22: 191–203.

    CAS  PubMed  Google Scholar 

  151. Gasior SL, Wakeman TP, Xu B, Deininger PL . The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol 2006; 357: 1383–1393.

    CAS  PubMed  Google Scholar 

  152. Belgnaoui SM, Gosden RG, Semmes OJ, Haoudi A . Human LINE-1 retrotransposon induces DNA damage and apoptosis in cancer cells. Cancer Cell Int 2006; 6: 13.

    PubMed  Google Scholar 

  153. Lin C, Yang L, Tanasa B, Hutt K, Ju B, Ohgi K et al. Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell 2009; 139: 1069–1083.

    CAS  PubMed  Google Scholar 

  154. Morse B, Rotherg PG, South VJ, Spandorfer JM, Astrin SM . Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma. Nature 1988; 333: 87–90.

    CAS  Google Scholar 

  155. Miki Y, Nishisho I, Horii A, Miyoshi Y, Utsunomiya J, Kinzler KW et al. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res 1992; 52: 643–645.

    CAS  Google Scholar 

  156. Chen L, Dahlstrom JE, Chandra A, Board P, Rangasamy D . Prognostic value of LINE-1 retrotransposon expression and its subcellular localization in breast cancer. Breast Cancer Res Treat 2012; 136: 129–142.

    CAS  PubMed  Google Scholar 

  157. Lee E, Iskow R, Yang L, Gokcumen O, Haseley P, Luquette LJ et al. Landscape of somatic retrotransposition in human cancers. Science 2012; 337: 967–971.

    CAS  PubMed  Google Scholar 

  158. Helman E, Lawrence MS, Stewart C, Sougnez C, Getz G, Meyerson M . Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res 2014; 24: 1053–1063.

    CAS  PubMed  Google Scholar 

  159. Wolff EM, Byun H-M, Han HF, Sharma S, Nichols PW, Siegmund KD et al. Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet 2010; 6: e1000917.

    PubMed  Google Scholar 

  160. Rodić N, Burns KH . Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLoS Genet 2013; 9: e1003402.

    PubMed  Google Scholar 

  161. Cruickshanks HA, Tufarelli C . Isolation of cancer-specific chimeric transcripts induced by hypomethylation of the LINE-1 antisense promoter. Genomics 2009; 94: 397–406.

    CAS  PubMed  Google Scholar 

  162. Cooke SL, Shlien A, Marshall J, Pipinikas CP, Martincorena I, Tubio JMC et al. Processed pseudogenes acquired somatically during cancer development. Nat Commun 2014; 5: 3644.

    PubMed  Google Scholar 

  163. Costello JF, Frühwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 2000; 24: 132–138.

    CAS  PubMed  Google Scholar 

  164. Raouf A, Sun Y, Chatterjee S, Basak P . The biology of human breast epithelial progenitors. Semin Cell Dev Biol 2012; 23: 606–612.

    CAS  PubMed  Google Scholar 

  165. Shehata M, Teschendorff A, Sharp G, Novcic N, Russell IA, Avril S et al. Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland. Breast Cancer Res 2012; 14: R134.

    CAS  PubMed  Google Scholar 

  166. Tao L, van Bragt MPA, Laudadio E, Li Z . Lineage tracing of mammary epithelial cells using cell-type-specific cre-expressing adenoviruses. Stem Cell Rep 2014; 2: 770–779.

    CAS  Google Scholar 

  167. Šale S, Lafkas D, Artavanis-Tsakonas S . Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 2013; 15: 451–460.

    PubMed  Google Scholar 

  168. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009; 15: 907–913.

    CAS  Google Scholar 

  169. Molyneux G, Geyer FC, Magnay F-A, McCarthy A, Kendrick H, Natrajan R et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 2010; 7: 403–417.

    CAS  Google Scholar 

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Acknowledgements

The research for DVB was supported by the Agency for Science, Technology and Research (Singapore) and for AE and DVB by the Foundation ARC (France).

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Emelyanov, A., Bulavin, D. Wip1 phosphatase in breast cancer. Oncogene 34, 4429–4438 (2015). https://doi.org/10.1038/onc.2014.375

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