Increased Expression of Mitotic Checkpoint Genes in Breast Cancer Cells with Chromosomal Instability
Purpose: Most breast cancers have chromosomal instability that seems related to defective mitotic spindle checkpoints. Because the molecular basis of this defect is unknown, we evaluated breast cancer cell lines and tissues for possible defects involving the major mitotic checkpoint genes responsibl...
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Published in | Clinical cancer research Vol. 12; no. 2; pp. 405 - 410 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Philadelphia, PA
American Association for Cancer Research
15.01.2006
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Subjects | |
Online Access | Get full text |
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Summary: | Purpose: Most breast cancers have chromosomal instability that seems related to defective mitotic spindle checkpoints. Because the
molecular basis of this defect is unknown, we evaluated breast cancer cell lines and tissues for possible defects involving
the major mitotic checkpoint genes responsible for maintaining chromosomal stability.
Experimental Design: We analyzed sequences and expression levels (RNA and protein) of eight major spindle checkpoint genes ( MAD1L1, MAD2L1, MAD2L2, BUB1, BUB1B, BUB3, CDC20 , and TTK ) in a panel of 12 breast cancer cell lines, most with established genetic instability and defective spindle damage checkpoint
response. mRNA levels of these genes were also measured in primary tumor samples, and immunohistochemical staining was used
to evaluate BUB1B protein levels in a panel of 270 additional cases of breast cancer.
Results: No functionally significant sequence variations were found for any of the eight genes in the breast cancer cell lines with
chromosomal instability. More surprisingly, the mRNA and protein levels for these checkpoint genes are significantly higher
in the genetically unstable breast cancer cell lines and in high-grade primary breast cancer tissues than in the stable (and
checkpoint proficient) MCF-10A and normal mammary epithelial cells, or in normal breast tissues. In fact, overexpression of
the BUB1B protein is a marker that recognizes nearly 80% of breast cancers in paraffin-embedded tissues.
Conclusions: Defective mitotic spindle checkpoints in breast cancer are most likely not caused by low expression or mutations of these
eight checkpoint genes. High levels of these particular transcripts could represent a cellular compensation for defects in
other molecular components of the mitotic spindle damage checkpoint, and increased expression of these genes might be markers
of breast cancers with chromosomal instability. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-05-0903 |