This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoon, D.-S. Articles by Gabrielson, E. Search for Related Content PubMed PubMed Citation Articles by Yoon, D.-S. Articles by Gabrielson, E.

(American Journal of Pathology. 2002;161:391-397.)
© 2002 American Society for Investigative Pathology

Short Communications

Variable Levels of Chromosomal Instability and Mitotic Spindle Checkpoint Defects in Breast Cancer

Dae-Sung Yoon^*, Robert P. Wersto, Weibo Zhou^*, Francis J. Chrest, Elizabeth S. Garrett^*, Teag Kyu Kwon and Edward Gabrielson^*

From the Departments of Pathology and Oncology,^*Johns Hopkins University School of Medicine, Baltimore, Maryland; The Gerontology Research Center,National Institute on Aging, Baltimore, Maryland; and the Department of Immunology,Keimyung University School of Medicine, Taegu, Korea

Cytogenetic analyses have revealed that many aneuploid breast cancers have cell-to-cell variations of chromosome copy numbers, suggesting that these neoplasms have instability of chromosome numbers. To directly test for possible chromosomal instability in this disease, we used fluorescent in situ hybridization to monitor copy numbers of multiple chromosomes in cultures of replicating breast cancer-derived cell lines and nonmalignant breast epithelial cells. While most (7 of 9) breast cancer cell lines tested are highly unstable with regard to chromosome copy numbers, others (2 of 9 cell lines) have a moderate level of instability that is higher than the "background" level of normal mammary epithelial cells and MCF-10A cells, but significantly less than that seen in the highly unstable breast cancer cell lines. To evaluate the potential role of a defective mitotic spindle checkpoint as a cause of this chromosomal instability, we used flow cytometry to monitor the response of cells to nocodazole-induced mitotic spindle damage. All cell lines with high levels of chromosomal instability have defective mitotic spindle checkpoints, whereas the cell lines with moderate levels of chromosomal instability (and the stable normal mammary cells and MCF10A cells) arrest in G₂ when challenged with nocodazole. Notably, the extent of mitotic spindle checkpoint deficiency and chromosome numerical instability in these cells is unrelated to the presence or absence of p53 mutations. Our results provide direct evidence for chromosomal instability in breast cancer and show that this instability occurs at variable levels among cells from different cancers, perhaps reflecting different functional classes of chromosomal instability. High levels of chromosomal instability are likely related to defective mitotic checkpoints but not to p53 mutations.

This article has been cited by other articles:

				A. M. Abukhdeir, M. I. Vitolo, P. Argani, A. M. De Marzo, B. Karakas, H. Konishi, J. P. Gustin, J. Lauring, J. P. Garay, C. Pendleton, et al. Tamoxifen-stimulated growth of breast cancer due to p21 loss PNAS, January 8, 2008; 105(1): 288 - 293. [Abstract] [Full Text] [PDF]

				Y. Niikura, A. Dixit, R. Scott, G. Perkins, and K. Kitagawa BUB1 mediation of caspase-independent mitotic death determines cell fate J. Cell Biol., July 10, 2007; 178(2): 283 - 296. [Abstract] [Full Text] [PDF]

				B. Yuan, Y. Xu, J.-H. Woo, Y. Wang, Y. K. Bae, D.-S. Yoon, R. P. Wersto, E. Tully, K. Wilsbach, and E. Gabrielson Increased Expression of Mitotic Checkpoint Genes in Breast Cancer Cells with Chromosomal Instability Clin. Cancer Res., January 15, 2006; 12(2): 405 - 410. [Abstract] [Full Text] [PDF]

				E. C. Dietze, M. L. Bowie, K. Mrozek, L. E. Caldwell, C. Neal, R. J. Marjoram, M. M. Troch, G. R. Bean, K. K. Yokoyama, C. A. Ibarra, et al. CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5 J. Cell Sci., November 1, 2005; 118(21): 5005 - 5022. [Abstract] [Full Text] [PDF]

				D. L. Morse, H. Gray, C. M. Payne, and R. J. Gillies Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells Mol. Cancer Ther., October 1, 2005; 4(10): 1495 - 1504. [Abstract] [Full Text] [PDF]

				C. Vogel, A. Kienitz, R. Muller, and H. Bastians The Mitotic Spindle Checkpoint Is a Critical Determinant for Topoisomerase-based Chemotherapy J. Biol. Chem., February 11, 2005; 280(6): 4025 - 4028. [Abstract] [Full Text] [PDF]

				E. A. Lee, M. K. Keutmann, M. L. Dowling, E. Harris, G. Chan, and G. D. Kao Inactivation of the mitotic checkpoint as a determinant of the efficacy of microtubule-targeted drugs in killing human cancer cells Mol. Cancer Ther., June 1, 2004; 3(6): 661 - 669. [Abstract] [Full Text] [PDF]