Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability

Bibo Yuan, Yi Xu, Ju Hyung Woo, Yunyue Wang, Young Kyung Bae, Dae Sung Yoon, Robert P. Wersto, Ellen Tully, Kathleen Wilsbach, Edward Gabrielson

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)405-410
Number of pages6
JournalClinical Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Jan 15 2006

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M Phase Cell Cycle Checkpoints
Chromosomal Instability
Breast Neoplasms
Genes
Cell Line
Proteins
Breast
Messenger RNA
Paraffin
Research Design
Epithelial Cells
RNA
Staining and Labeling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. / Yuan, Bibo; Xu, Yi; Woo, Ju Hyung; Wang, Yunyue; Bae, Young Kyung; Yoon, Dae Sung; Wersto, Robert P.; Tully, Ellen; Wilsbach, Kathleen; Gabrielson, Edward.

In: Clinical Cancer Research, Vol. 12, No. 2, 15.01.2006, p. 405-410.

Research output: Contribution to journalArticle

Yuan, B, Xu, Y, Woo, JH, Wang, Y, Bae, YK, Yoon, DS, Wersto, RP, Tully, E, Wilsbach, K & Gabrielson, E 2006, 'Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability', Clinical Cancer Research, vol. 12, no. 2, pp. 405-410. https://doi.org/10.1158/1078-0432.CCR-05-0903
Yuan, Bibo ; Xu, Yi ; Woo, Ju Hyung ; Wang, Yunyue ; Bae, Young Kyung ; Yoon, Dae Sung ; Wersto, Robert P. ; Tully, Ellen ; Wilsbach, Kathleen ; Gabrielson, Edward. / Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 2. pp. 405-410.
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abstract = "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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AU - Xu, Yi

AU - Woo, Ju Hyung

AU - Wang, Yunyue

AU - Bae, Young Kyung

AU - Yoon, Dae Sung

AU - Wersto, Robert P.

AU - Tully, Ellen

AU - Wilsbach, Kathleen

AU - Gabrielson, Edward

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N2 - 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.

AB - 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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