Abstract
The development and progression of aggressive breast cancer is characterized by genomic instability leading to multiple genetic defects, phenotypic diversity, chemoresistance, and poor outcome. Centrosome abnormalities have been implicated in the origin of chromosomal instability through the development of multipolar mitotic spindles. Breast tumor centrosomes display characteristic structural abnormalities, termed centrosome amplification, including: increase in centrosome number and volume, accumulation of excess pericentriolar material, supernumerary centrioles, and inappropriate phosphorylation of centrosome proteins. In addition, breast tumor centrosomes also show functional abnormalities characterized by inappropriate centrosome duplication during the cell cycle and nucleation of unusually large microtubule arrays. These observations have important implications for understanding the mechanisms underlying genomic instability and loss of cell polarity in cancer. This review focuses on the coordination of the centrosome, DNA, and cell cycles in normal cells and their deregulation resulting in centrosome amplification and chromosomal instability in the development and progression of breast cancer.
Similar content being viewed by others
REFERENCES
Wilson E. B. (1925). The Cell in Development and Heredit y, 3rd edn. Macmillan, New York.
M. Kirschner and T. Mitchison (1986). Beyond self-assembly: From microtubules to morphogenesis. Cell 45:329-342.
M. Bornens (2002). Centrosome composition and micro-tubule anchoring mechanisms. Curr. Opin. Cell Biol. 14:25- 34.
R. E. Palazzo (2003). Centrosome and spindle pole body dynamics: A review of the EMBO/EMBL Conference on Centrosomes and Spindle Pole Bodies, Heidelberg, September 13-17, Cell Motil. Cytoskeleton 54:148-154.
S. J. Doxsey (2001). Centrosomes as command centres for cellular control. Nat. Cell Biol. 3:E105-E108.
G. Sluder and E. H. Hinchcliffe (2000). The coordination of centrosome reproduction with nuclear events during the cell cycle. Curr. Top. Dev. Biol. 49:267-289.
J. L. Salisbury (2003). Centrosomes: Coiled-coils organize the cell center. Curr. Biol. 13:R88–R90.
J. L. Salisbury (2003). Centrosome size is controlled by centriolar SAS-4. Trends Cell Biol. 13:340-343.
J. L. Salisbury (2004). Centrosomes: sfi1p and centrin unravel a structural riddle. Curr. Biol. 14:R27–R29.
J. S. Andersen, C. J. Wilkinson, T. Mayor, P. Mortensen, E. A. Nigg, and M. Mann (2003). Proteomic characteriza-tion of the human centrosome by protein correlation profiling. Nature 426:570-574.
S. Dutcher (2001). Motile organelles: The importance of specific tubulin isoforms. Curr. Biol. 11:R419-R22.
S. K. Dutcher (2001). The tubulin fraternity: Alpha to eta. Curr. Opin. Cell Biol. 13:49-54.
D. Mazia (1987). The chromosome cycle and the centrosome cycle in the mitotic cycle. Int. Rev. Cytol. 100:49-92.
Y. Bobinnec, A. Khodjakov, L. M. Mir, C. L. Rieder, B. Edde, and M. Bornens (1998). Centriole disassembly in vivo and its effect on centrosome structure and function in vertebrate cells. J. Cell Biol. 143:1575-1589.
M. Kirkham, T. Muller-Reichert, K. Oegema, S. Grill, and A. A. Hyman (2003). SAS-4 is a C. elegans centriolar protein that controls centrosome size. Cell 112:575-587.
S. Leidel and P. Gonczy (2003). SAS-4 is essential for centro-some duplication in C. elegans and is recruited to daughter centrioles once per cell cycle. Dev. Cell 4:431-439.
S. J. Doxsey, P. Stein, L. Evans, P. D. Calarco, and M. Kirschner (1994). Pericentrin, a highly conserved cen-trosome protein involved in microtubule organization. Cell 76:639-650.
J. B. Dictenberg, W. Zimmerman, C. A. Sparks, A. Young, C. Vidair, Y. Zheng, et al(1998). Pericentrin and gamma-tubulin form a protein complex and are organized into a novel lattice at the centrosome. J. Cell Biol. 141:163- 174.
T. Ohta, R. Essner, J.-H. Ryu, R. E. Palazzo, Y. Uetake, and R. Kuriyama (2002). Characterization of Cep135, a novel coiled-coil centrosomal protein involved in microtubule organization in mammalian cells. J. Cell Biol. 156:87-100.
G. Keryer, R. M. Rios, B. F. Landmark, B. Skalhegg, S. M. Lohmann, and M. Bornens (1993). A high-affinity binding protein for the regulatory subunit of cAMP-dependent protein kinase II in the centrosome of human cells. Exp. Cell Res. 204:230-240.
O. Witczak, B. S. Skalhegg, G. Keryer, M. Bornens, K. Tasken, T. Jahnsen, et al(1999). Cloning and characteriza-tion of a cDNA encoding an A-kinase anchoring protein located in the centrosome, AKAP450. EMBO J. 18:1858-1868.
V. Bouckson-Castaing, M. Moudjou, D. J. Ferguson, S. Mucklow, Y. Belkaid, G. Milon, et al(1996). Molecular characterisation of ninein, a new coiled-coil protein of the centrosome. J. Cell Sci. 109:179-190.
A. Young, J. B. Dictenberg, A. Purohit, R. Tuft, and S. J. Doxsey (2000). Cytoplasmic dynein-mediated assembly of pericentrin and gamma tubulin onto centrosomes. Mol. Biol. Cell 11:2047-2056.
D. Diviani, L. K. Langeberg, S. J. Doxsey, and J. D. Scott (2000). Pericentrin anchors protein kinase A at the centro-some through a newly identified RII-binding domain. Curr. Biol. 10:417-420.
J. V. Kilmartin (2003). Sfi1p has conserved centrin-binding sites and an essential function in budding yeast spindle pole body duplication. J. Cell Biol. 162:1211-1221.
A. T. Baron, V. J. Suman, E. Nemeth, and J. L. Salisbury (1994). The pericentriolar lattice of PtK2 cells exhibits temperature and calcium-modulated behavior. J. Cell Sci. 107:2993-3003.
A. T. Baron, T. M. Greenwood, C. W. Bazinet, and J. L. Salisbury (1992). Centrin is a component of the peri-centriolar lattice. Biol. Cell 76:383-388.
D. R. Kellogg (1989). Centrosomes. Organizing cytoplasmic events. Nature 340:99-100.
I. R. Adams and J. V. Kilmartin (2000). Spindle pole body duplication: A model for centrosome duplication? Trends Cell Biol. 10:329-335.
D. Wheatley (1982). The Centriole: A Central Enigma of Cell Biolog y, Elsevier Biomedical Press, Amsterdam.
A. Khodjakov and C. L. Rieder (2001). Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J. Cell Biol. 153:237-242.
M. Piel, J. Nordberg, U. Euteneuer, and M. Bornens (2001). Centrosome-dependent exit of cytokinesis in animal cells. Science 291:1550-1553.
A. Khodjakov, C. L. Rieder, G. Sluder, G. Cassels, O. Sibon, and C.-L. Wang (2002). De novo formation of centrosomes in vertebrate cells arrested during S phase. J. Cell Biol. 158:1171-1181.
W. F. Marshall, Y. Vucica, and J. L. Rosenbaum (2001). Kinetics and regulation of de novo centriole assembly. Implications for the mechanism of centriole duplication. Curr. Biol. 11:308-317.
W. F. Marshall (1999). No centriole, no centrosome. Trends Cell Biol. 9:94.
E. H. Hinchcliffe, C. Li, E. A. Thompson, J. L. Maller, and G. Sluder (1999). Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283:851-854.
K. R. Lacey, P. K. Jackson, and T. Stearns (1999). Cyclin-dependent kinase control of centrosome duplication. Proc. Natl. Acad. Sci. U.S.A. 96:2817-2822.
Y. Matsumoto, K. Hayashi, and E. Nishida (1999). Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells. Curr. Biol. 9:429-432.
A. D'Assoro, R. Busby, K. Suino, E. Delva, G. Almodovar-Mercado, H. Johnson, et al. (in press). Genotoxic stress leads to centrosome amplification in breast cancer cell lines that have an inactive G1/S cell cycle checkpoint. Oncogene 23:4068-4075.
W. S. el-Deiry, T. Tokino, V. E. Velculescu, D. B. Levy, R. Parsons, J.M. Trent,et al. (1993). WAF1, a potential me-diator of p53 tumor suppression. Cell 75:817-825.
J.W. Harper, G.R. Adami, N. Wei, K. Keyomarsi,and S. J. Elledge (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805- 816.
E. Bailly, J. Pines, T. Hunter, and M. Bornens (1992). Cytoplasmic accumulation of cyclin B1 in human cells: Association with a detergent-resistant compartment and with the centrosome. J. Cell Sci. 101:529-545.
A. Debec and C. Montmory (1992). Cyclin B is associated with centrosomes in Drosophila mitotic cells. Biol. Cell 75:121-126.
F. Verde, J. C. Labbe, M. Doree, and E. Karsenti (1990). Regulation of microtubule dynamics by cdc2 protein ki-nase in cell-free extracts of Xenopus eggs. Nature 343:233- 238.
F. Verde, M. Dogterom, E. Stelzer, E. Karsenti, and S. Leibler (1992). Control of microtubule dynamics and length by cyclin A-and cyclin B-dependent kinases in Xeno-pus egg extracts. J. Cell Biol. 118:1097-1108.
S. M. Keezer and D. M. Gilbert (2002). Sensitivity of the origin decision point to specific inhibitors of cellular signaling and metabolism. Exp. Cell Res. 273:54-64.
M. Okuda (2002). The role of nucleophosmin in centrosome duplication. Oncogene 21:6170-6174.
A. M. Fry, T. Mayor, and E. A. Nigg (2000). Regulating centrosomes by protein phosphorylation. Curr. Top. Dev. Biol. 49:291-312.
D. D. Vandre and G. G. Borisy (1989). Anaphase onset and dephosphorylation of mitotic phosphoproteins occur concomitantly. J. Cell Sci. 94:245-258.
D. D. Vandre, Y. Feng, and M. Ding (2000). Cell cycle-dependent phosphorylation of centrosomes: Localization of phosphopeptide specific antibodies to the centrosome. Microsc. Res. Tech. 49:458-466.
P. N. Rao, J. Y. Zhao, R. K. Ganju, and C. L. Ashorn (1989). Monoclonal antibody against the centrosome. J. Cell Sci. 93:63-69.
W. Lutz, W. L. Lingle, D. McCormick, T. M. Greenwood, and J. L. Salisbury (2001). Phosphorylation of centrin during the cell cycle and its role in centriole separation preceding centrosome duplication. J. Biol. Chem. 276:20774-20780.
W. L. Lingle, W. H. Lutz, J. N. Ingle, N. J. Maihle, and J. L. Salisbury (1998). Centrosome hypertrophy in human breast tumors: Implications for genomic stability and cell polarity. Proc. Natl. Acad. Sci. U.S.A. 95:2950-2955.
H. Zhou, J. Kuang, L. Zhong, W. L. Kuo, J. W. Gray, A. Sahin, et al. (1998). Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat. Genet. 20:189-193.
Y. Miyoshi, K. Iwao, C. Egawa, and S. Noguchi (2001). Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int. J. Cancer 92:370-373.
H. Katayama, H. Zhou, Q. Li, M. Tatsuka, and S. Sen (2001). Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and Protein Phosphatase 1 through mitotic cell division cycle. J. Biol. Chem. 276:46219- 46224.
P. Meraldi, J. Lukas, A. Fry, J. Bartek, and E. Nigg (1999). Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat. Cell Biol. 1:88-93.
R. Balczon, L. Bao, W. E. Zimmer, K. Brown, R. P. Zinkowski, and B. R. Brinkley (1995). Dissociation of cen-trosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells. J. Cell Biol. 130:105-115.
K. Fukasawa, T. Choi, R. Kuriyama, S. Rulong, and G. F. Vande Woude (1996). Abnormal centrosome amplification in the absence of p53. Science 271:1744-1747.
K. L. Murphy and J. M. Rosen (2000). Mutant p53 and ge-nomic instability in a transgenic mouse model of breast cancer. Oncogene 19:1045-1051.
P. Tarapore, Y. Tokuyama, H. F. Horn, and K. Fukasawa (2001). Difference in the centrosome duplication regulatory activity among p53 “hot spot” mutants: Potential role of Ser 315 phosphorylation-dependent centrosome binding of p53. Oncogene 20:6851-6863.
C. Mantel, S. E. Braun, S. Reid, O. Henegariu, L. Liu, G. Hangoc, et al. (1999). p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells. Blood 93:1390-1398.
P. Tarapore, H. F. Horn, Y. Tokuyama, and K. Fukasawa (2001). Direct regulation of the centrosome duplication cy-cle by the p53-p21Waf1/Cip1 pathway. Oncogene 20:3173- 3184.
J. G. Mussman, H. F. Horn, P. E. Carroll, M. Okuda, P. Tarapore, L. A. Donehower, et al. (2000). Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression. Oncogene 19:1635- 1646.
L. A. Donehower, M. Harvey, B. L. Slagle, M. J. McArthur, C. A. Montgomery, Jr., J. S. Butel, et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215-221.
J. R. Eshleman, G. Casey, M. E. Kochera, W. D. Sedwick, S. E. Swinler, M. L. Veigl, et al. (1998). Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Onco-gene 17:719-725.
C. Lengauer, K. Kinzler, and B. Vogelstein (1997). Genetic instability in colorectal cancers. Nature 386:623-627.
W. L. Lingle, S. L. Barrett, V. C. Negron, A. B. D'Assoro, K. Boeneman, W. Liu, et al. (2002). Centrosome amplification drives chromosomal instability in breast tumor development. Proc. Natl. Acad. Sci. U.S.A. 99:1978-1983.
C. X. Deng and S. G. Brodie (2000). Roles of BRCA1 and its interacting proteins. Bioessays 22:728-737.
L. C. Hsu and R. L. White (1998). BRCA1 is associated with the centrosome during mitosis. Proc. Natl. Acad. Sci. U.S.A. 95:12983-12988.
X. Xu, Z. Weaver, S. P. Linke, C. Li, J. Gotay, X. W. Wang, et al. (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.
G. G. Maul, D. E. Jensen, A. M. Ishov, M. Herlyn, and F. J. Rauscher 3rd. (1998). Nuclear redistribution of BRCA1 during viral infection. Cell Growth Differ. 9:743-755.
A. Tutt, A. Gabriel, D. Bertwistle, F. Connor, H. Paterson, J. Peacock, et al. (1999). Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9:1107-1110.
M. B. Kastan, Q. Zhan, W. S. el-Deiry, F. Carrier, T. Jacks, W. V. Walsh, et al. (1992). A mammalian cell cycle check-point pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71:587-597.
X. W. Wang, Q. Zhan, J. D. Coursen, M. A. Khan, H. U. Kontny, L. Yu, et al. (1999). GADD45 induction of a G2/M cell cycle checkpoint. Proc. Natl. Acad. Sci. U.S.A. 96:3706-3711.
M. C. Hollander, M. S. Sheikh, D. V. Bulavin, K. Lundgren, L. Augeri-Henmueller, R. Shehee, et al. (1999). Genomic instability in Gadd45a-deficient mice. Nat. Genet. 23:176-184.
B. R. Brinkley (2001). Managing the centrosome numbers game: From chaos to stability in cancer cell division. Trends Cell Biol. 11:18-21.
L. M. Gustafson, L. L. Gleich, K. Fukasawa, J. Chadwell, M. A. Miller, P. J. Stambrook, et al. (2000). Centrosome hyperamplification in head and neck squamous cell carcinoma: A potential phenotypic marker of tumor aggressiveness. Laryngoscope 110:1798-1801.
K. K. Kuo, N. Sato, K. Mizumoto, N. Maehara, H. Yonemasu, C. G. Ker, et al. (2000). Centrosome abnormalities in human carcinomas of the gallbladder and intrahepatic and extrahepatic bile ducts. Hepatology 31:59-64.
G. A. Pihan, A. Purohit, J. Wallace, H. Knecht, B. Woda, P. Quesenberry, et al. (1998). Centrosome defects and genetic instability in malignant tumors. Cancer Res. 58:3974-3985.
N. Sato, K. Mizumoto, M. Nakamura, K. Nakamura, M. Kusumoto, H. Niiyama, et al. (1999). Centrosome abnormalities in pancreatic ductal carcinoma. Clin. Cancer Res. 5:963-970.
R. G. Weber, J. M. Bridger, A. Benner, D. Weisenberger, V. Ehemann, G. Reifenberger, et al. (1998). Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations. Cytogenet Cell Genet 83:266- 269.
A. B. D'Assoro, W. L. Lingle, and J. L. Salisbury (2002). Centrosome amplification and the development of cancer. Oncogene 21:6146-6153.
W. L. Lingle and J. L. Salisbury (1999). Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am. J. Pathol. 155:1941-1951.
P. Meraldi, R. Honda, and E. A. Nigg (2002). Aurora-A over-expression reveals tetraploidization as a major route to cen-trosome amplification in p53 -/- cells. EMBO J. 21:483-492.
J. L. Salisbury, W. L. Lingle, R. A. White, L. E. Cordes, and S. Barrett (1999). Microtubule nucleating capacity of centro-somes in tissue sections. J. Histochem. Cytochem. 47:1265- 1274.
A. B. D'Assoro, S. L. Barrett, C. Folk, V. C. Negron, K. Boeneman, and R. C. Busby, et al. (2002). Amplified centrosomes in breast cancer: A potential indicator of tumor aggressiveness. Breast Cancer Res. Treat. 75:25-34.
J. Mendelin, M. Grayson, T. Wallis, and D. W. Visscher (1999). Analysis of chromosome aneuploidy in breast. carcinoma progression by using fluorescence in situ hybridization. Lab. Invest. 79:387-393.
M. Tirkkonen, M. Tanner, R. Karhu, A. Kallioniemi, J. Isola, and O. P. Kallioniemi (1998). Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosomes Cancer 21:177-184.
C. Lengauer, K. W. Kinzler, and B. Vogelstein (1998). Genetic instabilities in human cancers. Nature 396:643- 649.
T. Boveri (1914). Zur Frage der Entstehung maligner Tumore n, Fischer Verlag, Jena, Germany (1929 English translation by M. Boveri reprinted as The Origin of Malignant Tumors, The Williams and Wilkins Co., Baltimore).
G. A. Pihan, A. Purohit, J. Wallace, R. Malhotra, L. Liotta, and S. J. Doxsey (2001). Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res. 61:2212-2219.
C. W. Elston and I. O. Ellis (1991). Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 19:403-410.
R. Engers and H. E. Gabbert (2000). Mechanisms of tumor metastasis: Cell biological aspects and clinical implications. J. Cancer Res. Clin. Oncol. 126:682-692.
P. L. Fitzgibbons, D. L. Page, D. Weaver, A. D. Thor, D. C. Allred, G. M. Clark, et al. (2000). Prognostic factors in breast cancer. College of American Pathologists Consensus Statement Arch. Pathol. Lab. Med. 124:966-978.
D. L. Page, R. Gray, D. C. Allred, L. G. Dressler, A. K. Hatfield, S. Martino, et al. (2001). Prediction of node-negative breast cancer outcome by histologic grading and S-phase analysis by flow cytometry: An Eastern Cooperative Oncology Group Study (2192). Am.J.Clin.Oncol. 24:10-18.
S. Sigurdsson, S. K. Bodvarsdottir, K. Anamthawat-Jonsson, M. Steinarsdottir, J. G. Jonasson, H. M. Ogmundsdottir, et al. (2000). p53 abnormality and chromosomal instability in the same breast tumor cells. Cancer Genet. Cytogenet. 121:150- 155.
C. Lavarino, V. Corletto, A. Mezzelani, G. Della Torre, C. Bartoli, C. Riva, et al. (1998). Detection of TP53 mutation, loss of heterozygosity and DNA content in fine-needle aspirates of breast carcinoma. Br.J.Cancer77:125-130.
T. Sauer, K. Beraki, P. W. Jebsen, E. Ormerod, and O. Naess (1998). Numerical aberrations of chromosome 17 in interphase cell nuclei of breast carcinoma cells: Lack of correla-tion with abnormal expression of p53, neu and nm23 protein. APMIS 106:921-927.
S. Chiba, M. Okuda, J. G. Mussman, and K. Fukasawa (2000). Genomic convergence and suppression of centrosome hyper-amplification in primary p53 -/- cells in prolonged culture. Exp. Cell Res. 258:310-321.
P. E. Carroll, M. Okuda, H. F. Horn, P. Biddinger, P. J. Stambrook, L. L. Gleich, et al. (1999). Centrosome hyperamplification in human cancer: Chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 18:1935-1944.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Salisbury, J.L., D'Assoro, A.B. & Lingle, W.L. Centrosome Amplification and the Origin of Chromosomal Instability in Breast Cancer. J Mammary Gland Biol Neoplasia 9, 275–283 (2004). https://doi.org/10.1023/B:JOMG.0000048774.27697.30
Issue Date:
DOI: https://doi.org/10.1023/B:JOMG.0000048774.27697.30