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    Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas

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    Authors
    Pihan, German A.
    Wallace, Jan
    Zhou, Yening
    Doxsey, Stephen J.
    UMass Chan Affiliations
    Program in Molecular Medicine
    Department of Pathology
    Document Type
    Journal Article
    Publication Date
    2003-03-22
    Keywords
    Breast Neoplasms
    Carcinoma in Situ
    Centrosome
    Cervical Intraepithelial Neoplasia
    *Chromosome Aberrations
    Chromosome Segregation
    Female
    Humans
    Immunohistochemistry
    Male
    Mitotic Spindle Apparatus
    Precancerous Conditions
    Prostatic Neoplasms
    Uterine Cervical Neoplasms
    Medical Molecular Biology
    Oncology
    Pathology
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    Abstract
    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.
    Source
    Cancer Res. 2003 Mar 15;63(6):1398-404.
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/40773
    PubMed ID
    12649205
    Related Resources
    Link to article in PubMed
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    UMass Chan Faculty and Researcher Publications

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