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Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues

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Abstract

Centrosomes, the main microtubule-organizing centers in most animal cells, are of crucial importance for the assembly of a bipolar mitotic spindle and subsequent faithful segregation of chromosomes into two daughter cells. Centrosome abnormalities can be found in virtually all cancer types and have been linked to chromosomal instability (CIN) and tumorigenesis. Although our knowledge on centrosome structure, replication, and amplification has greatly increased within recent years, still only very little is known on nature, causes, and consequences of centrosome aberrations in primary tumor tissues. In this review, we summarize our current insights into the mechanistic link between centrosome aberrations, aneuploidy, CIN and tumorigenesis. Mechanisms of induction and cellular consequences of aneuploidy, tetraploidization and CIN, as well as origin and effects of supernumerary centrosomes will be discussed. In addition, animal models for both CIN and centrosome amplification will be outlined. Finally, we describe approaches to exploit centrosome amplification, aneuploidy and CIN for novel and specific anticancer treatment strategies based on the modulation of chromosome missegregation rates.

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Abbreviations

17-AAG:

17-N-allylamino-17-demethoxygeldanamycin

AICAR:

5-aminoimidazole-4-carboxamide ribonucleotide

AMPK:

Adenosine monophosphate-activated protein kinase

APC/C:

Anaphase-promoting complex/cyclosome

Bub3/Rae1:

Mitotic checkpoint protein BUB3

BubR1:

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta

CDC20:

Cell-division cycle protein 20

CDK2:

Cyclin-dependent kinase 2

CENP-E:

Centromere-associated protein E

CEP170:

Centrosomal protein 170kDa

CIN:

Chromosomal instability

Eg5:

Kinesin family member 11

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ERBB2:

Receptor tyrosine-protein kinase erbB-2

HPV:

Human Papillomavirus

HSET:

KIFC1, kinesin family member C1

HSF1:

Heat shock factor protein 1

HSP90:

Heat shock protein 90

ILK:

Integrin-linked kinase

LOH:

Loss of heterozygosity

Mad1:

Mitotic arrest deficient 1

Mad2:

Mitotic arrest deficient 2

MEF:

Mouse embryonic fibroblast

MPS1:

Monopolar spindle 1

MTOC:

Microtubule-organizing center

MVA:

Mosaic variegated aneuploidy

NPM1:

Nucleophosmin

P53:

Tumor protein p53

PARP:

Poly (ADP) ribose polymerase

PCM:

Pericentriolar material

PLK4:

Polo-like kinase 4

ROS:

Reactive oxygen species

SAC:

Spindle assembly checkpoint

SAS4:

Spindle assembly abnormal protein 4

SAS6:

Spindle assembly abnormal protein 6

STIL:

SCL/TAL1 interrupting locus

UbcH10:

Ubiquitin-conjugating enzyme E2 C

References

  • Alieva IB, Vorobjev IA (1991) Induction of multipolar mitoses in cultured cells: decay and restructuring of the mitotic apparatus and distribution of centrioles. Chromosoma 100:532–542

    Article  CAS  PubMed  Google Scholar 

  • Andreassen PR, Lohez OD, Lacroix FB, Margolis RL (2001) Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol Biol Cell 12:1315–1328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009) Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 486:95–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Babu JR, Jeganathan KB, Baker DJ, Wu X, Kang-Decker N, van Deursen JM (2003) Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J Cell Biol 160:341–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker DJ, Jin F, Jeganathan KB, van Deursen JM (2009) Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterogeneity. Cancer Cell 16(6):475–486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L, van Ree JH, Crespo-Diaz R, Reyes S, Seaburg L, Shapiro V, Behfar A, Terzic A, van de Sluis B, van Deursen JM (2013) Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15(1):96–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakhoum SF, Compton DA (2012) Chromosomal instability and cancer: a complex relationship with therapeutic potential. J Clin Invest 122:1138–1143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakhoum SF, Kabeche L, Wood MD, Laucius CD, Qu D, Laughney AM, Reynolds GE, Louie RJ, Phillips J, Chan DA, Zaki BI, Murnane JP, Petritsch C, Compton DA (2015) Numerical chromosomal instability mediates susceptibility to radiation treatment. Nat Commun 6:5990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balbas-Martinez C, Sagrera A, Carrillo-de-Santa-Pau E, Earl J, Márquez M, Vazquez M, Lapi E, Castro-Giner F, Beltran S, Bayés M, Carrato A, Cigudosa JC, Domínguez O, Gut M, Herranz J, Juanpere N, Kogevinas M, Langa X, López-Knowles E, Lorente JA, Lloreta J, Pisano DG, Richart L, Rico D, Salgado RN, Tardón A, Chanock S, Heath S, Valencia A, Losada A, Gut I, Malats N, Real FX (2013) Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat Genet 45:1464–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basto R, Brunk K, Vinadogrova T, Peel N, Franz A, Khodjakov A, Raff JW (2008) Centrosome amplification can initiate tumorigenesis in flies. Cell 133:1032–1042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506

    Article  CAS  PubMed  Google Scholar 

  • Bazzi H, Anderson KV (2014) Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo. Proc Natl Acad Sci U S A 111(15):E1491–E1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beghini A, Ripamonti CB, Castorina P, Pezzetti L, Doneda L, Cairoli R, Morra E, Larizza L (2000) Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. Cancer Genet Cytogenet 119:26–31

    Article  CAS  PubMed  Google Scholar 

  • Bennett RA, Izumi H, Fukasawa K (2004) Induction of centrosome amplification and chromosome instability in p53-null cells by transient exposure to subtoxic levels of S-phase-targeting anticancer drugs. Oncogene 23:6823–6829

    Article  CAS  PubMed  Google Scholar 

  • Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho Y-J, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao M-S, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bettencourt-Dias M, Glover DM (2007) Centrosome biogenesis and function: centrosomics brings new understanding. Nat Rev Mol Cell Biol 8:451–463

    Article  CAS  PubMed  Google Scholar 

  • Bianchi AB, Aldaz CM, Conti CJ (1990) Nonrandom duplication of the chromosome bearing a mutated Ha-ras-1 allele in mouse skin tumors. Proc Natl Acad Sci U S A 87:6902–6906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bourke E, Dodson H, Merdes A, Cuffe L, Zachos G, Walker M, Gillespie D, Morrison CG (2007) DNA damage induces Chk1-dependent centrosome amplification. EMBO Rep 8:603–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boveri T (1887) Über die Befruchtung der Eier von Ascaris megalocephala. Sitz-Ber Ges Morph Phys München 3:71–80

    Google Scholar 

  • Boveri T (1888) Zellen-Studien II. Die Befruchtung und Teilung des Eies von Ascaris megalocephala. Jena Z Med Naturwiss 22:685–882

    Google Scholar 

  • Boveri T (2008) Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci 121(Suppl 1):1–84

    Article  PubMed  Google Scholar 

  • Bowen D, Groves MJ, Burnett AK, Patel Y, Allen C, Green C, Gale RE, Hills R, Linch DC (2008) TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia 23:203–206

    Article  PubMed  CAS  Google Scholar 

  • Castellanos E, Dominguez P, Gonzalez C (2008) Centrosome dysfunction in drosophila neural stem cells causes tumors that are not due to genome instability. Curr Biol 18:1209–1214

    Article  CAS  PubMed  Google Scholar 

  • Castiel A, Visochek L, Mittelman L, Dantzer F, Izraeli S, Cohen-Armon M (2011) A phenanthrene derived PARP inhibitor is an extra-centrosomes de-clustering agent exclusively eradicating human cancer cells. BMC Cancer 11:412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan JY (2011) A clinical overview of centrosome amplification in human cancers. Int J Biol Sci 7:1122–1144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cimini D, Tanzarella C, Degrassi F (1999) Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14:563–568

    Article  CAS  PubMed  Google Scholar 

  • D’Assoro AB, Busby R, Suino K, Delva E, Almodovar-Mercado GJ, Johnson H, Folk C, Farrugia DJ, Vasile V, Stivala F, Salisbury JL (2004) Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint. Oncogene 23:4068–4075

    Article  PubMed  CAS  Google Scholar 

  • Dai W, Wang Q, Liu T, Swamy M, Fang Y, Xie S, Mahmood R, Yang YM, Xu M, Rao CV (2004) Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res 64(2):440–445

    Article  CAS  PubMed  Google Scholar 

  • David A, Liu FY, Tibelius A, Vulprecht J, Wald D, Rothermel U, Ohana R, Seitel A, Metzger J, Ashery-Padan R, Meinzer H-P, Gröne H-J, Izraeli S, Krämer A (2014) Lack of centrioles and primary cilia in STIL−/− mouse embryos. Cell Cycle 13(18):2859–2868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dewhurst SM, McGranahan N, Burrell RA, Rowan AJ, Grönroos E, Endesfelder D, Joshi T, Mouradov D, Gibbs P, Ward RL, Hawkins NJ, Szallasi Z, Sieber OM, Swanton C (2014) Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov 4:175–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, Alessi DR, Dunlop MG (2012) Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastrenterology 142(1504), e3

    Google Scholar 

  • Dodson H, Bourke E, Jeffers LJ, Vagnarelli P, Sonoda E, Takeda S, Earnshaw WC, Merdes A, Morrison C (2004) Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM. EMBO J 23:3864–3873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dodson H, Wheatley SP, Morrison CG (2007) Involvement of centrosome amplification in radiation-induced mitotic catastrophe. Cell Cycle 6:364–370

    Article  CAS  PubMed  Google Scholar 

  • Dückert H, Pries V, Khedkar V, Menninger S, Bruss H, Bird AW, Maliga Z, Brockmeyer A, Janning P, Hyman A, Grimme S, Schürmann M, Preut H, Hübel K, Ziegler S, Kumar K, Waldmann H (2012) Natural product-inspired cascade synthesis yields modulators of centrosome integrity. Nat Chem Biol 8:179–184

    Article  CAS  Google Scholar 

  • Duensing S (2005) A tentative classification of centrosome abnormalities in cancer. Cell Biol Int 29:352–359

    Article  CAS  PubMed  Google Scholar 

  • Duensing S (2015) Analysis of centrosomes in human cancer. Methods Cell Biol 129:51–60

    Article  PubMed  Google Scholar 

  • Duensing S, Duensing A, Crum CP, Münger K (2001a) Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype. Cancer Res 61(6):2356–2360

    CAS  PubMed  Google Scholar 

  • Duensing S, Duensing A, Flores ER, Do A, Lambert PF, Münger K (2001b) Centrosome abnormalities and genomic instability by episomal expression of human papillomavirus type 16 in raft cultures of human keratinocytes. J Virol 75(16):7712–7716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duensing S, Duensing A, Lee DC, Edwards KM, Piboonniyom S-O, Manuel E, Skaltsounis L, Meijer L, Münger K (2004) Cyclin-dependent kinase inhibitor indirubin-3′-oxime selectively inhibits human papillomavirus type 16 E7-induced numerical centrosome anomalies. Oncogene 23:8206–8215

    Article  CAS  PubMed  Google Scholar 

  • Duensing A, Liu Y, Perdreau SA, Kleylein-Sohn J, Nigg EA, Duensing S (2007) Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates. Oncogene 26:6280–6288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duensing A, Chin A, Wang L, Kuan S-F, Duensing S (2008) Analysis of centrosome overduplication in correlation to cell division errors in high-risk human papillomavirus (HPV)-associated anal neoplasms. Virology 372:157–164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duesberg P, Rausch C, Rasnick D, Hehlmann R (1998) Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci U S A 95:13692–13697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duijf PHG, Benezra R (2013) The cancer biology of whole-chromosome instability. Oncogene 32:4727–4736

    Article  CAS  PubMed  Google Scholar 

  • Dürrbaum M, Kuznetsova AY, Passerini V, Stingele S, Stoehr G, Storchová Z (2014) Unique features of the transcriptional response to model aneuploidy in human cells. BMC Genomics 15:139

    Article  PubMed  PubMed Central  Google Scholar 

  • Faggioli F, Vezzoni P, Montagna C (2011) Single-cell analysis of ploidy and centrosomes underscores the peculiarity of normal hepatocytes. PLoS One 6, e26080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fielding AB, Dedhar S (2009) The mitotic functions of integrin-linked kinase. Cancer Metastasis Rev 28:99–111

    Article  PubMed  Google Scholar 

  • Fielding AB, Lim S, Montgomery K, Dobreva I, Dedhar S (2011) A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. Oncogene 30:521–534

    Article  CAS  PubMed  Google Scholar 

  • Fischer J, Palmedo G, von Knobloch R, Bugert P, Prayer-Galetti T, Pagano F, Kovacs G (1998) Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. Oncogene 17:733–739

    Article  CAS  PubMed  Google Scholar 

  • Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G, Sandgren J, Diaz de Ståhl T, Zaghlool A, Giedraitis V, Lannfelt L, Score J, Cross NC, Absher D, Janson ET, Lindgren CM, Morris AP, Ingelsson E, Lind L, Dumanski JP (2014) Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat Genet 46(6):624–628

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D (2005) Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043–1047

    Article  CAS  PubMed  Google Scholar 

  • Fukasawa K (2007) Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer 7:911–924

    Article  CAS  PubMed  Google Scholar 

  • Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF (1996) Abnormal centrosome amplification in the absence of p53. Science 271:1744–1747

    Article  CAS  PubMed  Google Scholar 

  • Galeotti G (1893) Beitrag zum Studium des Chromatins in den Epithelzellen der Carcinome. Beitr Pathol Anat Allg Pathol 14:249–271

    Google Scholar 

  • Galloway SM, Buckton KE (1978) Aneuploidy and ageing: chromosome studies on a random sample of the population using G-banding. Cytogenet Cell Genet 20(1–6):78–95

    Article  CAS  PubMed  Google Scholar 

  • Ganem NJ (2016) The interplay between centrosomes and the Hippo tumor suppressor pathway. Chromosom Res. doi:10.1007/s10577-015-9502-8

  • Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. Nature 460:278–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganem NJ, Cornils H, Chiu S-Y, O’Rourke KP, Arnaud J, Yimlamai D, Théry M, Camargo FD, Pellman D (2014) Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158:833–848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gascoigne KE, Taylor SS (2008) Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14:111–122

    Article  CAS  PubMed  Google Scholar 

  • Giam M, Rancati G (2015) Aneuploidy and chromosomal instability in cancer: a jackpot to chaos. Cell Div 10:3

    Article  PubMed  PubMed Central  Google Scholar 

  • Gisselsson D, Jin Y, Lindgren D, Persson J, Gisselsson L, Hanks S, Sehic D, Mengelbier LH, Øra I, Rahman N, Mertens F, Mitelman F, Mandahl N (2010) Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis. Proc Natl Acad Sci U S A 107(47):20489–20493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, Polyak K, Brugge JS, Théry M, Pellman D (2014) Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510(7503):167–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goepfert TM, Adigun YE, Zhong L, Gay J, Medina D, Brinkley WR (2002) Centrosome amplification and overexpression of Aurora A are early events in rat mammary carcinogenesis. Cancer Res 62(14):4115–4122

    CAS  PubMed  Google Scholar 

  • Gordon DJ, Resio B, Pellman D (2012) Causes and consequences of aneuploidy in cancer. Nat Rev Genet 13:189–203

    CAS  PubMed  Google Scholar 

  • Greaves M (2015) Evolutionary determinants of cancer. Cancer Discov 5:806–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481:306–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grisendi S, Mecucci C, Falini B, Pandolfi PP (2006) Nucleophosmin and cancer. Nat Rev Cancer 6:493–505

    Article  CAS  PubMed  Google Scholar 

  • Guarguaglini G, Duncan PI, Stierhof YD, Holmström T, Duensing S, Nigg EA (2005) The forkhead-associated domain protein Cep170 interacts with polo-like kinase 1 and serves as a marker for mature centrioles. Mol Biol Cell 16(3):1095–1107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo G, Sun X, Chen C, Wu S, Huang P, Li Z, Dean M, Huang Y, Jia W, Zhou Q, Tang A, Yang Z, Li X, Song P, Zhao X, Ye R, Zhang S, Lin Z, Qi M, Wan S, Xie L, Fan F, Nickerson ML, Zou X, Hu X, Xing L, Lv Z, Mei H, Gao S, Liang C, Gao Z, Lu J, Yu Y, Liu C, Li L, Fang X, Jiang Z, Yang J, Li C, Zhao X, Chen J, Zhang F, Lai Y, Lin Z, Zhou F, Chen H, Chan HC, Tsang S, Theodorescu D, Li Y, Zhang X, Wang J, Yang H, Gui Y, Wang J, Cai Z (2013) Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation. Nat Genet 45:1459–1463

    Article  CAS  PubMed  Google Scholar 

  • Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D, Kidd A, Méhes K, Nash R, Robin N, Shannon N, Tolmie J, Swansbury J, Irrthum A, Douglas J, Rahman N (2004) Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet 36(11):1159–1161

    Article  CAS  PubMed  Google Scholar 

  • Hansemann L (1890) Über asymmetrische Zelltheilung in Epithelkrebsen und deren biologische Bedeutung. Virchows Arch Pathol Anat Physiol Klin Med 119:299–326

    Article  Google Scholar 

  • Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG (2012) The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336(6083):918–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holland AJ, Cleveland DW (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 13:501–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holland AJ, Fachinetti D, Zhu Q, Bauer M, Verma IM, Nigg EA, Cleveland DW (2012) The autoregulated instability of polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes Dev 26:2684–2689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM Jr, Li Y, Ward JM, Benezra R, Jeang KT (2007) Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res 67(1):160–166

    Article  CAS  PubMed  Google Scholar 

  • Jacobs PA, Court Brown WM, Doll R (1961) Distribution of human chromosome counts in relation to age. Nature 191:1178–1180

    Article  CAS  PubMed  Google Scholar 

  • Jacobs PA, Brunton M, Court Brown WM, Doll R, Goldstein H (1963) Change of human chromosome count distribution with age: evidence for a sex differences. Nature 197:1080–1081

    Article  CAS  PubMed  Google Scholar 

  • Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B, Hutchinson A, Deng X, Liu C, Horner MJ, Cullen M, Epstein CG, Burdett L, Dean MC, Chatterjee N, Sampson J, Chung CC, Kovaks J, Gapstur SM, Stevens VL, Teras LT, Gaudet MM, Albanes D, Weinstein SJ, Virtamo J, Taylor PR, Freedman ND, Abnet CC, Goldstein AM, Hu N, Yu K, Yuan JM, Liao L, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Aldrich MC, Amos C, Blot WJ, Bock CH, Gillanders EM, Harris CC, Haiman CA, Henderson BE, Kolonel LN, Le Marchand L, McNeill LH, Rybicki BA, Schwartz AG, Signorello LB, Spitz MR, Wiencke JK, Wrensch M, Wu X, Zanetti KA, Ziegler RG, Figueroa JD, Garcia-Closas M, Malats N, Marenne G, Prokunina-Olsson L, Baris D, Schwenn M, Johnson A, Landi MT, Goldin L, Consonni D, Bertazzi PA, Rotunno M, Rajaraman P, Andersson U, Beane Freeman LE, Berg CD, Buring JE, Butler MA, Carreon T, Feychting M, Ahlbom A, Gaziano JM, Giles GG, Hallmans G, Hankinson SE, Hartge P, Henriksson R, Inskip PD, Johansen C, Landgren A, McKean-Cowdin R, Michaud DS, Melin BS, Peters U, Ruder AM, Sesso HD, Severi G, Shu XO, Visvanathan K, White E, Wolk A, Zeleniuch-Jacquotte A, Zheng W, Silverman DT, Kogevinas M, Gonzalez JR, Villa O, Li D, Duell EJ, Risch HA, Olson SH, Kooperberg C, Wolpin BM, Jiao L, Hassan M, Wheeler W, Arslan AA, Bueno-de-Mesquita HB, Fuchs CS, Gallinger S, Gross MD, Holly EA, Klein AP, LaCroix A, Mandelson MT, Petersen G, Boutron-Ruault MC, Bracci PM, Canzian F, Chang K, Cotterchio M, Giovannucci EL, Goggins M, Hoffman Bolton JA, Jenab M, Khaw KT, Krogh V, Kurtz RC, McWilliams RR, Mendelsohn JB, Rabe KG, Riboli E, Tjønneland A, Tobias GS, Trichopoulos D, Elena JW, Yu H, Amundadottir L, Stolzenberg-Solomon RZ, Kraft P, Schumacher F, Stram D, Savage SA, Mirabello L, Andrulis IL, Wunder JS, Patiño García A, Sierrasesúmaga L, Barkauskas DA, Gorlick RG, Purdue M, Chow WH, Moore LE, Schwartz KL, Davis FG, Hsing AW, Berndt SI, Black A, Wentzensen N, Brinton LA, Lissowska J, Peplonska B, McGlynn KA, Cook MB, Graubard BI, Kratz CP, Greene MH, Erickson RL, Hunter DJ, Thomas G, Hoover RN, Real FX, Fraumeni JF Jr, Caporaso NE, Tucker M, Rothman N, Pérez-Jurado LA, Chanock SJ (2012) Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 44(6):651–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janssen A, Kops GJPL, Medema RH (2009) Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc Natl Acad Sci U S A 106:19108–19113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janssen A, van der Burg M, Szuhai K, Kops GJPL, Medema RH (2011) Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333:1895–1898

    Article  CAS  PubMed  Google Scholar 

  • Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM (2007) Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 179(2):255–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karna P, Rida PCG, Pannu V, Gupta KK, Dalton WB, Joshi H, Yang VW, Zhou J, Aneja R (2011) A novel microtubule-modulating noscapinoid triggers apoptosis by inducing spindle multipolarity via centrosome amplification and declustering. Cell Death Differ 18:632–644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawamura E, Fielding AB, Kannan N, Balgi A, Eaves CJ, Roberge M, Dedhar S (2013) Identification of novel small molecule inhibitors of centrosome clustering in cancer cells. Oncotarget 4:1763–1776

    Article  PubMed  PubMed Central  Google Scholar 

  • Keryer G, Ris H, Borisy GG (1984) Centriole distribution during tripolar mitosis in Chinese hamster ovary cells. J Cell Biol 98:2222–2229

    Article  CAS  PubMed  Google Scholar 

  • Kleylein-Sohn J, Pöllinger B, Ohmer M, Hofmann F, Nigg EA, Hemmings BA, Wartmann M (2012) Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET. J Cell Sci 125:5391–5402

    Article  CAS  PubMed  Google Scholar 

  • Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW, Swallow CJ (2005) Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet 37:883–888

    Article  CAS  PubMed  Google Scholar 

  • Koller PC (1947) Abnormal mitosis in tumours. Br J Cancer 1(1):38–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, Yoshida K, Okuno Y, Bando M, Nakato R, Ishikawa S, Sato-Otsubo A, Nagae G, Nishimoto A, Haferlach C, Nowak D, Sato Y, Alpermann T, Nagasaki M, Shimamura T, Tanaka H, Chiba K, Yamamoto R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Nakamaki T, Ishiyama K, Nolte F, Hofmann WK, Miyawaki S, Chiba S, Mori H, Nakauchi H, Koeffler HP, Aburatani H, Haferlach T, Shirahige K, Miyano S, Ogawa S (2013) Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 45:1232–1237

    Article  CAS  PubMed  Google Scholar 

  • Kong D, Farmer V, Shukla A, James J, Gruskin R, Kiriyama S, Loncarek J (2014) Centriole maturation requires regulated Plk1 activity during two consecutive cell cycles. J Cell Biol 206(7):855–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krämer A, Schweizer S, Neben K, Giesecke C, Kalla J, Katzenberger T, Benner A, Müller-Hermelink HK, Ho AD, Ott G (2003) Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin’s lymphoma. Leukemia 17(11):2207–2213

    Article  PubMed  CAS  Google Scholar 

  • Krämer A, Maier B, Bartek J (2011) Centrosome clustering and chromosomal (in)stability: a matter of life and death. Mol Oncol 5:324–335

    Article  PubMed  CAS  Google Scholar 

  • Kraus WL (2015) PARPs and ADP-ribosylation: 50 years … counting. Mol Cell 58:902–910

    Article  CAS  PubMed  Google Scholar 

  • Krzywicka-Racka A, Sluder G (2011) Repeated cleavage failure does not establish centrosome amplification in untransformed human cells. J Cell Biol 194:199–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuffer C, Kuznetsova AY, Storchová Z (2013) Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells. Chromosoma 122:305–318

    Article  CAS  PubMed  Google Scholar 

  • Kuznetsova AY, Seget K, Moeller GK, de Pagter MS, de Roos JADM, Dürrbaum M, Kuffer C, Müller S, Zaman GJR, Kloosterman WP, Storchová Z (2015) Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells. Cell Cycle 14(17):2810–2820

    Article  CAS  PubMed  Google Scholar 

  • Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M, Pellman D (2008) Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 22:2189–2203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lambrus BG, Uetake Y, Clutario KM, Daggubati V, Snyder M, Sluder G, Holland AJ (2015) p53 protects against genome instability following centriole duplication failure. J Cell Biol 210:63–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lanni JS, Jacks T (1998) Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol Cell Biol 18:1055–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laughney AM, Elizalde S, Genovese G, Bakhoum SF (2015) Dynamics of tumor heterogeneity derived from clonal karyotypic evolution. Cell Reprogram 12:809–820

    Article  CAS  Google Scholar 

  • Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP, Ling H, Hetrick KN, Pugh EW, Amos C, Wei Q, Wang LE, Lee JE, Barnes KC, Hansel NN, Mathias R, Daley D, Beaty TH, Scott AF, Ruczinski I, Scharpf RB, Bierut LJ, Hartz SM, Landi MT, Freedman ND, Goldin LR, Ginsburg D, Li J, Desch KC, Strom SS, Blot WJ, Signorello LB, Ingles SA, Chanock SJ, Berndt SI, Le Marchand L, Henderson BE, Monroe KR, Heit JA, de Andrade M, Armasu SM, Regnier C, Lowe WL, Hayes MG, Marazita ML, Feingold E, Murray JC, Melbye M, Feenstra B, Kang JH, Wiggs JL, Jarvik GP, McDavid AN, Seshan VE, Mirel DB, Crenshaw A, Sharopova N, Wise A, Shen J, Crosslin DR, Levine DM, Zheng X, Udren JI, Bennett S, Nelson SC, Gogarten SM, Conomos MP, Heagerty P, Manolio T, Pasquale LR, Haiman CA, Caporaso N, Weir BS (2012) Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 44(6):642–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leber B, Maier B, Fuchs F, Chi J, Riffel P, Anderhub S, Wagner L, Ho AD, Salisbury JL, Boutros M, Krämer A (2010) Proteins required for centrosome clustering in cancer cells. Sci Transl Med 2, 33ra38

    Article  PubMed  CAS  Google Scholar 

  • Lee AJX, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA, Downward J, Szallasi Z, Tomlinson IPM, Howell M, Kschischo M, Swanton C (2011) Chromosomal instability confers intrinsic multidrug resistance. Cancer Res 71:1858–1870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li M, Fang X, Wei Z, York JP, Zhang P (2009) Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. J Cell Biol 185(6):983–994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z, Han S, van Deursen JM, Zhang P (2010) The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci U S A 107:14188–14193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lingle WL, Lutz WH, Ingle JN, Maihle NJ, Salisbury JL (1998) Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity. Proc Natl Acad Sci U S A 95(6):2950–2955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lingle WL, Barrett SL, Negron VC, D’Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL (2002) Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A 99(4):1978–1983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lissa D, Senovilla L, Rello-Varona S, Vitale I, Michaud M, Pietrocola F, Boilève A, Obrist F, Bordenave C, Garcia P, Michels J, Jemaà M, Kepp O, Castedo M, Kroemer G (2014) Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention. Proc Natl Acad Sci U S A 111:3020–3025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Löffler H, Fechter A, Liu FY, Poppelreuther S, Krämer A (2013) DNA damage-induced centrosome amplification occurs via excessive formation of centriolar satellites. Oncogene 32:2963–2972

    Article  PubMed  CAS  Google Scholar 

  • Lohez OD, Reynaud C, Borel F, Andreassen PR, Margolis RL (2003) Arrest of mammalian fibroblasts in G1 in response to actin inhibition is dependent on retinoblastoma pocket proteins but not on p53. J Cell Biol 161:67–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maiato H, Logarinho E (2014) Mitotic spindle multipolarity without centrosome amplification. Nat Cell Biol 16:386–394

    Article  CAS  PubMed  Google Scholar 

  • Mardin BR, Isokane M, Cosenza MR, Krämer A, Ellenberg J, Fry AM, Schiebel E (2013) EGF-induced centrosome separation promotes mitotic progression and cell survival. Dev Cell 25:229–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marthiens V, Rujano MA, Pennetier C, Tessier S, Paul-Gilloteaux P, Basto R (2013) Centrosome amplification causes microcephaly. Nat Cell Biol 15:731–740

    Article  CAS  PubMed  Google Scholar 

  • Mason JM, Lin DC-C, Wei X, Che Y, Yao Y, Kiarash R, Cescon DW, Fletcher GC, Awrey DE, Bray MR, Pan G, Mak TW (2014) Functional characterization of CFI-400945, a polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell 26:163–176

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto Y, Hayashi K, Nishida E (1999) Cyclin-dependent kinase 2 (CDK2) is required for centrosome duplication in mammalian cells. Curr Biol 9(8):429–432

  • McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C (2012) Cancer chromosomal instability: therapeutic and diagnostic challenges. EMBO Rep 13:528–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meraldi P, Honda R, Nigg EA (2002) Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J 21(4):483–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty VV, Benezra R (2001) MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409:355–359

    Article  CAS  PubMed  Google Scholar 

  • Mitelman F, Johansson B, Mertens F (Eds) (2012) Mitelman database of chromosome aberrations and gene fusions in cancer. http://cgap.nci.nih.gov/Chromosomes /Mitelman

  • Mountain V, Simerly C, Howard L, Ando A, Schatten G, Compton DA (1999) The kinesin-related protein, HSET, opposes the activity of Eg5 and cross-links microtubules in the mammalian mitotic spindle. J Cell Biol 147:351–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mullee, Morrison (2016) Centrosomes in the DNA damage response—the hub outside of the centre. Chromosom Res. doi:10.1007/s10577-015-9503-7

  • Nakamura T, Saito H, Takekawa M (2013) SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nat Commun 4:1775

    Article  PubMed  CAS  Google Scholar 

  • Neben K, Giesecke C, Schweizer S, Ho AD, Krämer A (2003) Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile. Blood 101(1):289–291

    Article  CAS  PubMed  Google Scholar 

  • Nicholson JM, Cimini D (2013) Cancer karyotypes: survival of the fittest. Frontiers in Oncology 3:148

    Article  PubMed  PubMed Central  Google Scholar 

  • Nicholson JM, Macedo JC, Mattingly AJ, Wangsa D, Camps J, Lima V, Gomes AM, Doria S, Ried T, Logarinho E, Cimini D (2015) Chromosome mis-segregation and cytokinesis failure in trisomic human cells. Elife 4. doi: 10.7554

  • Nigg EA (2002) Centrosome aberrations: cause or consequence of cancer progression? Nat Rev Cancer 2(11):815–825

    Article  CAS  PubMed  Google Scholar 

  • Nishii K, Usui E, Katayama N, Lorenzo F, Nakase K, Kobayashi T, Miwa H, Mizutani M, Tanaka I, Nasu K, Dohy H, Kyo T, Taniwaki M, Ueda T, Kita K, Shiku H (2003) Characteristics of t(8;21) acute myeloid leukemia (AML) with additional chromosomal abnormality: concomitant trisomy 4 may constitute a distinctive subtype of t(8;21) AML. Leukemia 17:731–737

    Article  CAS  PubMed  Google Scholar 

  • Ochi T (2000) Induction of centrosome injury, multipolar spindles and multipolar division in cultured V79 cells exposed to dimethylarsinic acid: role for microtubules in centrosome dynamics. Mutat Res 454:21–33

    Article  CAS  PubMed  Google Scholar 

  • Ochi T (2002) Methylmercury, but not inorganic mercury, causes abnormality of centrosome integrity (multiple foci of gamma-tubulin), multipolar spindles and multinucleated cells without microtubule disruption in cultured Chinese hamster V79 cells. Toxicology 175:111–121

    Article  CAS  PubMed  Google Scholar 

  • Ogden A, Cheng A, Rida PCG, Pannu V, Osan R, Clewley R, Aneja R (2014) Quantitative multi-parametric evaluation of centrosome declustering drugs: centrosome amplification, mitotic phenotype, cell cycle and death. Cell Death Dis 5, e1204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okamoto Y, Ozaki T, Miyazaki K, Aoyama M, Miyazaki M, Nakagawara A (2003) UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme. Cancer Res 63:4167–4173

    CAS  PubMed  Google Scholar 

  • Oromendia AB, Dodgson SE, Amon A (2012) Aneuploidy causes proteotoxic stress in yeast. Genes Dev 26:2696–2708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pannu V, Rida PC, Celik B, Turaga RC, Ogden A, Cantuaria G, Gopalakrishnan J, Aneja R (2014) Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells. Cell Death Dis 5, e1538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paulsson K, Lilljebjörn H, Biloglav A, Olsson L, Rissler M, Castor A, Barbany G, Fogelstrand L, Nordgren A, Sjögren H, Fioretos T, Johansson B (2015) The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet 6:672–676

    Article  CAS  Google Scholar 

  • Pavelka N, Rancati G, Zhu J, Bradford WD, Saraf A, Florens L, Sanderson BW, Hattem GL, Li R (2010) Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468:321–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierre RV, Hoagland HC (1972) Age-associated aneuploidy: loss of Y chromosome from human bone marrow cells with aging. Cancer 30(4):889–894

    Article  CAS  PubMed  Google Scholar 

  • Pihan GA (2013) Centrosome dysfunction contributes to chromosome instability, chromoanagenesis, and genome reprograming in cancer. Front Oncol 3:277

    Article  PubMed  PubMed Central  Google Scholar 

  • Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P, Doxsey SJ (1998) Centrosome defects and genetic instability in malignant tumors. Cancer Res 58(17):3974–3985

    CAS  PubMed  Google Scholar 

  • Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ (2001) Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 61(5):2212–2219

    CAS  PubMed  Google Scholar 

  • Pihan GA, Wallace J, Zhou Y, Doxsey SJ (2003) Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res 63(6):1398–1404

    CAS  PubMed  Google Scholar 

  • Quintyne NJ, Reing JE, Hoffelder DR, Gollin SM, Saunders WS (2005) Spindle multipolarity is prevented by centrosomal clustering. Science 307:127–129

    Article  CAS  PubMed  Google Scholar 

  • Raab MS, Breitkreutz I, Anderhub S, Rønnest MH, Leber B, Larsen TO, Weiz L, Konotop G, Hayden PJ, Podar K, Fruehauf J, Nissen F, Mier W, Haberkorn U, Ho AD, Goldschmidt H, Anderson KC, Clausen MH, Krämer A (2012) GF-15, a novel inhibitor of centrosomal clustering, suppresses tumor cell growth in vitro and in vivo. Cancer Res 72:5374–5385

    Article  CAS  PubMed  Google Scholar 

  • Rape M, Kirschner MW (2004) Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature 432:588–595

    Article  CAS  PubMed  Google Scholar 

  • Rebacz B, Larsen TO, Clausen MH, Rønnest MH, Löffler H, Ho AD, Krämer A (2007) Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen. Cancer Res 67:6342–6350

    Article  CAS  PubMed  Google Scholar 

  • Ricke RM, van Ree JH, van Deursen JM (2008) Whole chromosome instability and cancer: a complex relationship. Trends Genet 24:457–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ried T, Hu Y, Difilippantonio MJ, Ghadimi BM, Grade M, Camps J (2012) The consequences of chromosomal aneuploidy on the transcriptome of cancer cells. Biochim Biophys Acta 1819:784–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ring D, Hubble R, Kirschner M (1982) Mitosis in a cell with multiple centrioles. J Cell Biol 94:549–556

    Article  CAS  PubMed  Google Scholar 

  • Roschke AV, Kirsch IR (2005) Targeting cancer cells by exploiting karyotypic complexity and chromosomal instability. Cell Cycle 4:679–682

    Article  CAS  PubMed  Google Scholar 

  • Roschke AV, Kirsch IR (2010) Targeting karyotypic complexity and chromosomal instability of cancer cells. Curr Drug Targets 11:1341–1350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roschke AV, Tonon G, Gehlhaus KS, McTyre N, Bussey KJ, Lababidi S, Scudiero DA, Weinstein JN, Kirsch IR (2003) Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res 63:8634–8647

    CAS  PubMed  Google Scholar 

  • Roschke AV, Lababidi S, Tonon G, Gehlhaus KS, Bussey K, Weinstein JN, Kirsch IR (2005) Karyotypic “state” as a potential determinant for anticancer drug discovery. Proc Natl Acad Sci U S A 102:2964–2969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rücker FG, Schlenk RF, Bullinger L, Kayser S, Teleanu V, Kett H, Habdank M, Kugler C-M, Holzmann K, Gaidzik VI, Paschka P, Held G, von Lilienfeld-Toal M, Lübbert M, Fröhling S, Zenz T, Krauter J, Schlegelberger B, Ganser A, Lichter P, Döhner K, Döhner H (2012) TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 119:2114–2121

    Article  PubMed  CAS  Google Scholar 

  • Saito T, Hama S, Izumi H, Yamasaki F, Kajiwara Y, Matsuura S, Morishima K, Hidaka T, Shrestha P, Sugiyama K, Kurisu K (2008) Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells. Br J Cancer 98:345–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakaushi S, Nishida K, Fukada T, Senda-Murata K, Oka S, Sugimoto K (2008) Differential responses of mitotic spindle pole formation to microtubule-stabilizing agents epothilones A and B at low concentrations. Cell Cycle 7:477–483

    Article  CAS  PubMed  Google Scholar 

  • Saladino C, Bourke E, Conroy PC, Morrison CG (2009) Centriole separation in DNA damage-induced centrosome amplification. Environ Mol Mutagen 50:725–732

    Article  CAS  PubMed  Google Scholar 

  • Santagata S, Mendillo ML, Tang YC, Subramanian A, Perley CC, Roche SP, Wong B, Narayan R, Kwon H, Koeva M, Amon A, Golub TR, Porco JA Jr, Whitesell L, Lindquist S (2013) Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341(6143):1238303

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Santaguida S, Amon A (2015) Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol 16:473–485

    Article  CAS  PubMed  Google Scholar 

  • Schneeweiss A, Sinn HP, Ehemann V, Khbeis T, Neben K, Krause U, Ho AD, Bastert G, Krämer A (2003) Centrosomal aberrations in primary invasive breast cancer are associated with nodal status and hormone receptor expression. Int J Cancer 107(3):346–352

    Article  CAS  PubMed  Google Scholar 

  • Sheltzer JM (2013) A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis. Cancer Res 73:6401–6412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheltzer JM, Blank HM, Pfau SJ, Tange Y, George BM, Humpton TJ, Brito IL, Hiraoka Y, Niwa O, Amon A (2011) Aneuploidy drives genomic instability in yeast. Science 333:1026–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheltzer JM, Torres EM, Dunham MJ, Amon A (2012) Transcriptional consequences of aneuploidy. Proc Natl Acad Sci U S A 109:12644–12649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiheido H, Terada F, Tabata N, Hayakawa I, Matsumura N, Takashima H, Ogawa Y, Du W, Yamada T, Shoji M, Sugai T, Doi N, Iijima S, Hattori Y, Yanagawa H (2012) A phthalimide derivative that inhibits centrosomal clustering is effective on multiple myeloma. PLoS One 7, e38878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shono M, Sato N, Mizumoto K, Maehara N, Nakamura M, Nagai E, Tanaka M (2001) Stepwise progression of centrosome defects associated with local tumor growth and metastatic process of human pancreatic carcinoma cells transplanted orthotopically into nude mice. Lab Investig 81(7):945–952

    Article  CAS  PubMed  Google Scholar 

  • Silkworth WT, Nardi IK, Scholl LM, Cimini D (2009) Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS One 4, e6564

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Silkworth WT, Nardi IK, Paul R, Mogilner A, Cimini D (2012) Timing of centrosome separation is important for accurate chromosome segregation. Mol Biol Cell 23(3):401–411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomon DA, Kim T, Diaz-Martinez LA, Fair J, Elkahloun AG, Harris BT, Toretsky JA, Rosenberg SA, Shukla N, Ladanyi M, Samuels Y, James CD, Yu H, Kim JS, Waldman T (2011) Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science 333:1039–1043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sotillo R, Hernando E, Díaz-Rodríguez E, Teruya-Feldstein J, Cordón-Cardo C, Lowe SW, Benezra R (2007) Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11:9–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sotillo R, Schvartzman J-M, Socci ND, Benezra R (2010) Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464:436–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stingele S, Stoehr G, Peplowska K, Cox J, Mann M, Storchova Z (2012) Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol Syst Biol 8:608

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stingele S, Stoehr G, Storchova Z (2013) Activation of autophagy in cells with abnormal karyotype. Autophagy 9:246–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swanton C, Nicke B, Schuett M, Eklund AC, Ng C, Li Q, Hardcastle T, Lee A, Roy R, East P, Kschischo M, Endesfelder D, Wylie P, Kim SN, Chen J-G, Howell M, Ried T, Habermann JK, Auer G, Brenton JD, Szallasi Z, Downward J (2009) Chromosomal instability determines taxane response. Proc Natl Acad Sci U S A 106:8671–8676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang Y-C, Williams BR, Siegel JJ, Amon A (2011) Identification of aneuploidy-selective antiproliferation compounds. Cell 144:499–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thol F, Bollin R, Gehlhaar M, Walter C, Dugas M, Suchanek KJ, Kirchner A, Huang L, Chaturvedi A, Wichmann M, Wiehlmann L, Shahswar R, Damm F, Göhring G, Schlegelberger B, Schlenk R, Döhner K, Döhner H, Krauter J, Ganser A, Heuser M (2014) Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood 123:914–920

    Article  CAS  PubMed  Google Scholar 

  • Thompson SL, Compton DA (2008) Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol 180:665–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thompson SL, Compton DA (2010) Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol 188:369–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tighe A, Johnson VL, Albertella M, Taylor SS (2001) Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep 2:609–614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Timonen S, Therman E (1950) The changes in the mitotic mechanism of human cancer cells. Cancer Res 10(7):431–439

    CAS  PubMed  Google Scholar 

  • Torres EM, Sokolsky T, Tucker CM, Chan LY, Boselli M, Dunham MJ, Amon A (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317:916–924

    Article  CAS  PubMed  Google Scholar 

  • Torres EM, Dephoure N, Panneerselvam A, Tucker CM, Whittaker CA, Gygi SP, Dunham MJ, Amon A (2010) Identification of aneuploidy-tolerating mutations. Cell 143:71–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uetake Y, Sluder G (2004) Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a “tetraploidy checkpoint”. J Cell Biol 165:609–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uetake Y, Sluder G (2010) Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. Curr Biol 20:1666–1671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • United Kingdom Cancer Cytogenetics Group (UKCCG) (1992) Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosom Cancer 5(1):83–88

    Article  Google Scholar 

  • van Ree JH, Jeganathan KB, Malureanu L, van Deursen JM (2010) Overexpression of the E2 ubiquitin-conjugating enzyme UbcH10 causes chromosome missegregation and tumor formation. J Cell Biol 188(1):83–100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Vitale I, Galluzzi L, Castedo M, Kroemer G (2011) Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol 12(6):385–392

    Article  CAS  PubMed  Google Scholar 

  • Vitrat N, Cohen-Solal K, Pique C, Le Couedic JP, Norol F, Larsen AK, Katz A, Vainchenker W, Debili N (1998) Endomitosis of human megakaryocytes are due to abortive mitosis. Blood 91(10):3711–3723

    CAS  PubMed  Google Scholar 

  • Wagner KW, Sapinoso LM, El-Rifai W, Frierson HF, Butz N, Mestan J, Hofmann F, Deveraux QL, Hampton GM (2004) Overexpression, genomic amplification and therapeutic potential of inhibiting the UbcH10 ubiquitin conjugase in human carcinomas of diverse anatomic origin. Oncogene 23:6621–6629

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Zhou Y-X, Qiao W, Tominaga Y, Ouchi M, Ouchi T, Deng C-X (2006) Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25:7148–7158

    Article  CAS  PubMed  Google Scholar 

  • Watts CA, Richards FM, Bender A, Bond PJ, Korb O, Kern O, Riddick M, Owen P, Myers RM, Raff J, Gergely F, Jodrell DI, Ley SV (2013) Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes. Chem Biol 20:1399–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver BAA, Cleveland DW (2006) Does aneuploidy cause cancer? Curr Opin Cell Biol 18:658–667

    Article  CAS  PubMed  Google Scholar 

  • Weaver BA, Cleveland DW (2008) The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell 14:431–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver BA, Cleveland DW (2009) The role of aneuploidy in promoting and suppressing tumors. J Cell Biol 185(6):935–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weaver Z, Montagna C, Xu X, Howard T, Gadina M, Brodie SG, Deng C-X, Ried T (2002) Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer. Oncogene 21:5097–5107

    Article  CAS  PubMed  Google Scholar 

  • Weaver BAA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW (2007) Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:25–36

    Article  CAS  PubMed  Google Scholar 

  • Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, Wartman LD, Lamprecht TL, Liu F, Xia J, Kandoth C, Fulton RS, McLellan MD, Dooling DJ, Wallis JW, Chen K, Harris CC, Schmidt HK, Kalicki-Veizer JM, Lu C, Zhang Q, Lin L, O’Laughlin MD, McMichael JF, Delehaunty KD, Fulton LA, Magrini VJ, McGrath SD, Demeter RT, Vickery TL, Hundal J, Cook LL, Swift GW, Reed JP, Alldredge PA, Wylie TN, Walker JR, Watson MA, Heath SE, Shannon WD, Varghese N, Nagarajan R, Payton JE, Baty JD, Kulkarni S, Klco JM, Tomasson MH, Westervelt P, Walter MJ, Graubert TA, DiPersio JF, Ding L, Mardis ER, Wilson RK (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150:264–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiktor A, Rybicki BA, Piao ZS, Shurafa M, Barthel B, Maeda K, Van Dyke DL (2000) Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosom Cancer 27(1):11–16

    Article  CAS  PubMed  Google Scholar 

  • Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA, Housman DE, Amon A (2008) Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322:703–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong C, Stearns T (2005) Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure. BMC Cell Biol 6:6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wong YL, Anzola JV, Davis RL, Yoon M, Motamedi A, Kroll A, Seo CP, Hsia JE, Kim SK, Mitchell JW, Mitchell BJ, Desai A, Gahman TC, Shiau AK, Oegema K (2015) Cell biology. Reversible centriole depletion with an inhibitor of polo-like kinase 4. Science 348:1155–1160

    Article  CAS  PubMed  Google Scholar 

  • Wright WE, Hayflick L (1972) Formation of anucleate and multinucleate cells in normal and SV40 transformed WI-38 by cytochalasin B. Exp Cell Res 74:187–194

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Mikule K, Wang W, Su N, Petteruti P, Gharahdaghi F, Code E, Zhu X, Jacques K, Lai Z, Yang B, Lamb ML, Chuaqui C, Keen N, Chen H (2013) Discovery and mechanistic study of a small molecule inhibitor for motor protein KIFC1. ACS Chem Biol 8:2201–2208

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3:389–395

    Article  CAS  PubMed  Google Scholar 

  • Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, Sanada M, Park MJ, Terui K, Suzuki H, Kon A, Nagata Y, Sato Y, Wang R, Shiba N, Chiba K, Tanaka H, Hama A, Muramatsu H, Hasegawa D, Nakamura K, Kanegane H, Tsukamoto K, Adachi S, Kawakami K, Kato K, Nishimura R, Izraeli S, Hayashi Y, Miyano S, Kojima S, Ito E, Ogawa S (2013) The landscape of somatic mutations in down syndrome-related myeloid disorders. Nat Genet 45:1293–1299

    Article  CAS  PubMed  Google Scholar 

  • Zacharaki P, Stephanou G, Demopoulos NA (2013) Comparison of the aneugenic properties of nocodazole, paclitaxel and griseofulvin in vitro. Centrosome defects and alterations in protein expression profiles. J Appl Toxicol 33:869–879

    Article  CAS  PubMed  Google Scholar 

  • Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, Lawrence MS, Zhang C-Z, Wala J, Mermel CH, Sougnez C, Gabriel SB, Hernandez B, Shen H, Laird PW, Getz G, Meyerson M, Beroukhim R (2013) Pan-cancer patterns of somatic copy number alteration. Nat Genet 45:1134–1140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaki BI, Suriawinata AA, Eastman AR, Garner KM, Bakhoum SF (2014) Chromosomal instability portends superior response of rectal adenocarcinoma to chemoradiation therapy. Cancer 120:1733–1742

    Article  CAS  PubMed  Google Scholar 

  • Zasadil LM, Andersen KA, Yeum D, Rocque GB, Wilke LG, Tevaarwerk AJ, Raines RT, Burkard ME, Weaver BA (2014) Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med 6, 229ra43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhang D, Hirota T, Marumoto T, Shimizu M, Kunitoku N, Sasayama T, Arima Y, Feng L, Suzuki M, Takeya M, Saya H (2004) Cre-loxP-controlled periodic Aurora-A overexpression induces mitotic abnormalities and hyperplasia in mammary glands of mouse models. Oncogene 23:8720–8730

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Pavelka N, Bradford WD, Rancati G, Li R (2012) Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet 8, e1002719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhuang Z, Park WS, Pack S, Schmidt L, Vortmeyer AO, Pak E, Pham T, Weil RJ, Candidus S, Lubensky IA, Linehan WM, Zbar B, Weirich G (1998) Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20:66–69

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Alwin Krämer.

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Cosenza, M.R., Krämer, A. Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues. Chromosome Res 24, 105–126 (2016). https://doi.org/10.1007/s10577-015-9505-5

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