Cancer Research Donn Young Sign up for Cancer Research eTOC's
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pihan, G. A.
Right arrow Articles by Doxsey, S. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pihan, G. A.
Right arrow Articles by Doxsey, S. J.
[Cancer Research 63, 1398-1404, March 15, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Centrosome Abnormalities and Chromosome Instability Occur Together in Pre-invasive Carcinomas1

German A. Pihan, Jan Wallace, Yening Zhou and Stephen J. Doxsey2

Departments of Pathology [G. A. P., J. W., Y. Z.] and Molecular Medicine [S. J. D.], University of Massachusetts Medical School, Worcester, Massachusetts 01605

Centrosomes play critical roles in processes that ensure proper segregation of chromosomes and maintain the genetic stability of human cells. They contribute to mitotic spindle organization and regulate aspects of cytokinesis and cell cycle progression. We and others have shown that centrosomes are abnormal in most aggressive carcinomas. Moreover, centrosome defects have been implicated in chromosome instability and loss of cell cycle control in invasive carcinoma. Others have suggested that centrosome defects only occur late in tumorigenesis and may not contribute to early steps of tumor development. To address this issue, we examined pre-invasive human carcinoma in situ lesions for centrosome defects and chromosome instability. We found that a significant fraction of precursor lesions to some of the most common human cancers had centrosome defects, including in situ carcinomas of the uterine cervix, prostate, and female breast. Moreover, centrosome defects occurred together with mitotic spindle defects, chromosome instability, and high cytologic grade. Because most pre-invasive lesions are not uniformly mutant for p53, the development of centrosome defects does not appear to require abrogation of p53 function. Our findings demonstrate that centrosome defects occur concurrently with chromosome instability and cytologic changes in the earliest identifiable step in human cancer. Our results suggest that centrosome defects may contribute to the earliest stages of cancer development through the generation of chromosome instability. This, together with ongoing structural changes in chromosomes, could accelerate accumulation of alleles carrying pro-oncogenic mutations and loss of alleles containing wild-type tumor suppressor genes and thus accelerate the genomic changes characteristic of carcinoma, the most prevalent human cancer.




This article has been cited by other articles:


Home page
 Hum ReprodHome page
M. Joffe
What has happened to human fertility?
Hum. Reprod., November 19, 2009; (2009) dep390v1.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
R. C. Eisman, M. A. S. Phelps, and T. C. Kaufman
Centrosomin: A Complex Mix of Long and Short Isoforms Is Required for Centrosome Function During Early Development in Drosophila melanogaster
Genetics, August 1, 2009; 182(4): 979 - 997.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. L. Prosser, K. R. Straatman, and A. M. Fry
Molecular Dissection of the Centrosome Overduplication Pathway in S-Phase-Arrested Cells
Mol. Cell. Biol., April 1, 2009; 29(7): 1760 - 1773.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
T. Liu, Y. Niu, Y. Yu, Y. Liu, and F. Zhang
Increased {gamma}-tubulin expression and P16INK4A promoter methylation occur together in preinvasive lesions and carcinomas of the breast
Ann. Onc., March 1, 2009; 20(3): 441 - 448.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Shimada, R. Sagae, J. Kobayashi, T. Habu, and K. Komatsu
Inactivation of the Nijmegen Breakage Syndrome Gene Leads to Excess Centrosome Duplication via the ATR/BRCA1 Pathway
Cancer Res., March 1, 2009; 69(5): 1768 - 1775.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger
Delocalization of the Microtubule Motor Dynein from Mitotic Spindles by the Human Papillomavirus E7 Oncoprotein Is Not Sufficient for Induction of Multipolar Mitoses
Cancer Res., November 1, 2008; 68(21): 8715 - 8722.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
J. Kim, Y.-L. Choi, A. Vallentin, B. S. Hunrichs, M. K. Hellerstein, D. M. Peehl, and D. Mochly-Rosen
Centrosomal PKC{beta}II and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis
Cancer Res., August 15, 2008; 68(16): 6831 - 6839.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
M. Kwon, S. A. Godinho, N. S. Chandhok, N. J. Ganem, A. Azioune, M. Thery, and D. Pellman
Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes
Genes & Dev., August 15, 2008; 22(16): 2189 - 2203.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
C. Man, J. Rosa, Y. L. Yip, A. L.-M. Cheung, Y. L. Kwong, S. J. Doxsey, and S. W. Tsao
Id1 Overexpression Induces Tetraploidization and Multiple Abnormal Mitotic Phenotypes by Modulating Aurora A
Mol. Biol. Cell, June 1, 2008; 19(6): 2389 - 2401.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
C. Didier, A. Merdes, J.-E. Gairin, and N. Jabrane-Ferrat
Inhibition of Proteasome Activity Impairs Centrosome-dependent Microtubule Nucleation and Organization
Mol. Biol. Cell, March 1, 2008; 19(3): 1220 - 1229.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
S. Bahmanyar, D. D. Kaplan, J. G. DeLuca, T. H. Giddings Jr., E. T. O'Toole, M. Winey, E. D. Salmon, P. J. Casey, W. J. Nelson, and A. I.M. Barth
{beta}-Catenin is a Nek2 substrate involved in centrosome separation
Genes & Dev., January 1, 2008; 22(1): 91 - 105.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Sankaran, D. E. Crone, R. E. Palazzo, and J. D. Parvin
Aurora-A Kinase Regulates Breast Cancer Associated Gene 1 Inhibition of Centrosome-Dependent Microtubule Nucleation
Cancer Res., December 1, 2007; 67(23): 11186 - 11194.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Biol. CellHome page
C. Kasbek, C.-H. Yang, A. M. Yusof, H. M. Chapman, M. Winey, and H. A. Fisk
Preventing the Degradation of Mps1 at Centrosomes Is Sufficient to Cause Centrosome Reduplication in Human Cells
Mol. Biol. Cell, November 1, 2007; 18(11): 4457 - 4469.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
C. M. Caldwell, R. A. Green, and K. B. Kaplan
APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice
J. Cell Biol., September 24, 2007; 178(7): 1109 - 1120.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. I. van de Wetering and C. M. Knudson
Chromosomal Instability and Supernumerary Centrosomes Represent Precursor Defects in a Mouse Model of T-Cell Lymphoma
Cancer Res., September 1, 2007; 67(17): 8081 - 8088.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. D. Slack, Z. Chen, A. D. Ludwig, J. Hicks, and J. M. Shohet
MYCN-Directed Centrosome Amplification Requires MDM2-Mediated Suppression of p53 Activity in Neuroblastoma Cells
Cancer Res., March 15, 2007; 67(6): 2448 - 2455.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J. Gu, Y. Gong, M. Huang, C. Lu, M. R. Spitz, and X. Wu
Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians
Carcinogenesis, February 1, 2007; 28(2): 350 - 355.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. Akao, H. Matsuyama, Y. Yamamoto, K. Sasaki, and K. Naito
Chromosome 20q13.2 Gain May Predict Intravesical Recurrence after Nephroureterectomy in Upper Urinary Tract Urothelial Tumors
Clin. Cancer Res., December 1, 2006; 12(23): 7004 - 7008.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
M. C Fleisch, C. A Maxwell, and M.-H. Barcellos-Hoff
The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs.
Endocr. Relat. Cancer, June 1, 2006; 13(2): 379 - 400.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
E. C. Y. Lee, A. Frolov, R. Li, G. Ayala, and N. M. Greenberg
Targeting aurora kinases for the treatment of prostate cancer.
Cancer Res., May 15, 2006; 66(10): 4996 - 5002.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Yamamoto, H. Matsuyama, S. Kawauchi, T. Furuya, X. P. Liu, K. Ikemoto, A. Oga, K. Naito, and K. Sasaki
Biological characteristics in bladder cancer depend on the type of genetic instability.
Clin. Cancer Res., May 1, 2006; 12(9): 2752 - 2758.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
W. J. Chng, G. J. Ahmann, K. Henderson, R. Santana-Davila, P. R. Greipp, M. A. Gertz, M. Q. Lacy, A. Dispenzieri, S. Kumar, S. V. Rajkumar, et al.
Clinical implication of centrosome amplification in plasma cell neoplasm
Blood, May 1, 2006; 107(9): 3669 - 3675.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
F. Suizu, A. Ryo, G. Wulf, J. Lim, and K. P. Lu
Pin1 Regulates Centrosome Duplication, and Its Overexpression Induces Centrosome Amplification, Chromosome Instability, and Oncogenesis
Mol. Cell. Biol., February 15, 2006; 26(4): 1463 - 1479.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
V. S. Golubkov, A. V. Chekanov, S. J. Doxsey, and A. Y. Strongin
Centrosomal Pericentrin Is a Direct Cleavage Target of Membrane Type-1 Matrix Metalloproteinase in Humans but Not in Mice: POTENTIAL IMPLICATIONS FOR TUMORIGENESIS
J. Biol. Chem., December 23, 2005; 280(51): 42237 - 42241.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
C. Zou, J. Li, Y. Bai, W. T. Gunning, D. E. Wazer, V. Band, and Q. Gao
Centrobin: a novel daughter centriole-associated protein that is required for centriole duplication
J. Cell Biol., November 7, 2005; 171(3): 437 - 445.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
V. S. Golubkov, S. Boyd, A. Y. Savinov, A. V. Chekanov, A. L. Osterman, A. Remacle, D. V. Rozanov, S. J. Doxsey, and A. Y. Strongin
Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) Exhibits an Important Intracellular Cleavage Function and Causes Chromosome Instability
J. Biol. Chem., July 1, 2005; 280(26): 25079 - 25086.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. Bergmann, B. Royer-Pokora, E. Fietze, K. Jurchott, B. Hildebrandt, D. Trost, F. Leenders, J.-C. Claude, F. Theuring, R. Bargou, et al.
YB-1 Provokes Breast Cancer through the Induction of Chromosomal Instability That Emerges from Mitotic Failure and Centrosome Amplification
Cancer Res., May 15, 2005; 65(10): 4078 - 4087.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. A. Maxwell, J. J. Keats, A. R. Belch, L. M. Pilarski, and T. Reiman
Receptor for Hyaluronan-Mediated Motility Correlates with Centrosome Abnormalities in Multiple Myeloma and Maintains Mitotic Integrity
Cancer Res., February 1, 2005; 65(3): 850 - 860.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. J. Li, S. J. Weroha, W. L. Lingle, D. Papa, J. L. Salisbury, and S. A. Li
Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats
PNAS, December 28, 2004; 101(52): 18123 - 18128.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
A. Tighe, V. L. Johnson, and S. S. Taylor
Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability
J. Cell Sci., December 15, 2004; 117(26): 6339 - 6353.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
B. L. Schneider and M. Kulesz-Martin
Destructive cycles: the role of genomic instability and adaptation in carcinogenesis
Carcinogenesis, November 1, 2004; 25(11): 2033 - 2044.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
T. Sun, X. Miao, J. Wang, W. Tan, Y. Zhou, C. Yu, and D. Lin
Functional Phe31Ile polymorphism in Aurora A and risk of breast carcinoma
Carcinogenesis, November 1, 2004; 25(11): 2225 - 2230.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. G. Hayward, R. B. Clarke, A. J. Faragher, M. R. Pillai, I. M. Hagan, and A. M. Fry
The Centrosomal Kinase Nek2 Displays Elevated Levels of Protein Expression in Human Breast Cancer
Cancer Res., October 15, 2004; 64(20): 7370 - 7376.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
L. M. Starita, Y. Machida, S. Sankaran, J. E. Elias, K. Griffin, B. P. Schlegel, S. P. Gygi, and J. D. Parvin
BRCA1-Dependent Ubiquitination of {gamma}-Tubulin Regulates Centrosome Number
Mol. Cell. Biol., October 1, 2004; 24(19): 8457 - 8466.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Yamamoto, H. Matsuyama, T. Furuya, A. Oga, S. Yoshihiro, M. Okuda, S. Kawauchi, K. Sasaki, and K. Naito
Centrosome Hyperamplification Predicts Progression and Tumor Recurrence in Bladder Cancer
Clin. Cancer Res., October 1, 2004; 10(19): 6449 - 6455.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. A. Nowak, F. Michor, N. L. Komarova, and Y. Iwasa
Evolutionary dynamics of tumor suppressor gene inactivation
PNAS, July 20, 2004; 101(29): 10635 - 10638.
[Abstract] [Full Text] [PDF]

Home page
 Mol Cancer ResHome page
C. Yun, H. Cho, S.-J. Kim, J.-H. Lee, S. Y. Park, G. K. Chan, and H. Cho
Mitotic Aberration Coupled With Centrosome Amplification Is Induced by Hepatitis B Virus X Oncoprotein via the Ras-Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Pathway
Mol. Cancer Res., March 1, 2004; 2(3): 159 - 169.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Chen, A. Purohit, E. Halilovic, S. J. Doxsey, and A. C. Newton
Centrosomal Anchoring of Protein Kinase C {beta}II by Pericentrin Controls Microtubule Organization, Spindle Function, and Cytokinesis
J. Biol. Chem., February 6, 2004; 279(6): 4829 - 4839.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.