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Increased expression of Mitotic Arrest Deficient-Like 1 (MAD1L1) is associated with poor prognosis and insensitive to Taxol treatment in breast cancer

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Abstract

Aneuploidy is a characteristic of human cancers, and recent studies have suggested that defects of mitotic checkpoints play a role in carcinogenesis. Mitotic Arrest Deficient-Like 1 (MAD1L1), whose altered expression is associated with chromosomal instability, is a checkpoint gene. We examined MAD1L1 protein expression from 461 breast cancer tissues and patients’ normal breast tissues by tissue microarray to study the correlation between the MAD1L1 expression and the clinicopathological features. MAD1L1 protein expression was significantly increased in the nuclei of cancer cells (28.4 %) compared with that in normal mammary cells (2.2 %), and was correlated with Her-2 status, cancer subtypes, p53 status, and age. High level of MAD1L1 expression in nuclei was associated with worse OS (p = 0.018). Furthermore, patients with high level of MAD1L1 expression (in nuclei) and undergone Taxol chemotherapy treatment have shorter overall survival than ones without Taxol treatment in this study (p = 0.026). In conclusion, our data demonstrated a significant correlation between nuclear expression of MAD1L1 protein and adverse prognosis in breast cancer. MAD1L1 might be used as a prognostic biomarker for breast cancer and expression of MAD1L1 in nuclei is also a predict biomarker of contraindication to pacilitaxel treatment in breast cancer.

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References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29. doi:10.3322/caac.20138

    Article  PubMed  Google Scholar 

  2. Olopade OI, Grushko TA, Nanda R, Huo D (2008) Advances in breast cancer: pathways to personalized medicine. Clin Cancer Res 14(24):7988–7999. doi:10.1158/1078-0432.CCR-08-1211

    Article  PubMed  CAS  Google Scholar 

  3. Tirkkonen M, Tanner M, Karhu R, Kallioniemi A, Isola J, Kallioniemi OP (1998) Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosom Cancer 21(3):177–184

    Article  PubMed  CAS  Google Scholar 

  4. Mendelin J, Grayson M, Wallis T, Visscher DW (1999) Analysis of chromosome aneuploidy in breast carcinoma progression by using fluorescence in situ hybridization. Lab Investig 79(4):387–393

    PubMed  CAS  Google Scholar 

  5. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392(6673):300–303. doi:10.1038/32688

    Article  PubMed  CAS  Google Scholar 

  6. Pihan GA, Doxsey SJ (1999) The mitotic machinery as a source of genetic instability in cancer. Semin Cancer Biol 9(4):289–302. doi:10.1006/scbi.1999.0131

    Article  PubMed  CAS  Google Scholar 

  7. Takahashi T, Haruki N, Nomoto S, Masuda A, Saji S, Osada H (1999) Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. Oncogene 18(30):4295–4300. doi:10.1038/sj.onc.1202807

    Article  PubMed  CAS  Google Scholar 

  8. Musacchio A, Salmon ED (2007) The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8(5):379–393. doi:10.1038/nrm2163

    Article  PubMed  CAS  Google Scholar 

  9. Rieder CL (2011) Mitosis in vertebrates: the G2/M and M/A transitions and their associated checkpoints. Chromosom Res 19(3):291–306. doi:10.1007/s10577-010-9178-z

    Article  Google Scholar 

  10. Li X, Nicklas RB (1995) Mitotic forces control a cell-cycle checkpoint. Nature 373(6515):630–632. doi:10.1038/373630a0

    Article  PubMed  CAS  Google Scholar 

  11. Rieder CL, Cole RW, Khodjakov A, Sluder G (1995) The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol 130(4):941–948

    Article  PubMed  CAS  Google Scholar 

  12. Rieder CL, Schultz A, Cole R, Sluder G (1994) Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J Cell Biol 127(5):1301–1310

    Article  PubMed  CAS  Google Scholar 

  13. Amon A (1999) The spindle checkpoint. Curr Opin Genet Dev 9(1):69–75

    Article  PubMed  CAS  Google Scholar 

  14. Sanchez Y, Bachant J, Wang H, Hu F, Liu D, Tetzlaff M, Elledge SJ (1999) Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science 286(5442):1166–1171

    Article  PubMed  CAS  Google Scholar 

  15. Chen RH, Brady DM, Smith D, Murray AW, Hardwick KG (1999) The spindle checkpoint of budding yeast depends on a tight complex between the Mad1 and Mad2 proteins. Mol Biol Cell 10(8):2607–2618

    Article  PubMed  CAS  Google Scholar 

  16. Iouk T, Kerscher O, Scott RJ, Basrai MA, Wozniak RW (2002) The yeast nuclear pore complex functionally interacts with components of the spindle assembly checkpoint. J Cell Biol 159(5):807–819. doi:10.1083/jcb.200205068

    Article  PubMed  CAS  Google Scholar 

  17. Campbell MS, Chan GK, Yen TJ (2001) Mitotic checkpoint proteins HsMAD1 and HsMAD2 are associated with nuclear pore complexes in interphase. J Cell Sci 114(Pt 5):953–963

    PubMed  CAS  Google Scholar 

  18. Howell BJ, McEwen BF, Canman JC, Hoffman DB, Farrar EM, Rieder CL, Salmon ED (2001) Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol 155(7):1159–1172. doi:10.1083/jcb.200105093

    Article  PubMed  CAS  Google Scholar 

  19. Musacchio A (2011) Spindle assembly checkpoint: the third decade. Philos Trans R Soc Lond B 366(1584):3595–3604. doi:10.1098/rstb.2011.0072

    Article  CAS  Google Scholar 

  20. Tsukasaki K, Miller CW, Greenspun E, Eshaghian S, Kawabata H, Fujimoto T, Tomonaga M, Sawyers C, Said JW, Koeffler HP (2001) Mutations in the mitotic check point gene, MAD1L1, in human cancers. Oncogene 20(25):3301–3305. doi:10.1038/sj.onc.1204421

    Article  PubMed  CAS  Google Scholar 

  21. 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. Clin Cancer Res 12(2):405–410. doi:10.1158/1078-0432.CCR-05-0903

    Article  PubMed  CAS  Google Scholar 

  22. Han S, Park K, Kim HY, Lee MS, Kim HJ, Kim YD, Yuh YJ, Kim SR, Suh HS (2000) Clinical implication of altered expression of Mad1 protein in human breast carcinoma. Cancer 88(7):1623–1632

    Article  PubMed  CAS  Google Scholar 

  23. Matkovic B, Juretic A, Separovic V, Novosel I, Separovic R, Gamulin M, Kruslin B (2008) Immunohistochemical analysis of ER, PR, HER-2, CK 5/6, p63 and EGFR antigen expression in medullary breast cancer. Tumori 94(6):838–844

    PubMed  Google Scholar 

  24. Hsu CY, Ho DM, Yang CF, Lai CR, Yu IT, Chiang H (2002) Interobserver reproducibility of Her-2/neu protein overexpression in invasive breast carcinoma using the DAKO HercepTest. Am J Clin Pathol 118(5):693–698. doi:10.1309/6ANB-QXCF-EHKC-7UC7

    Article  PubMed  CAS  Google Scholar 

  25. Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Der Pathologe 8(3):138–140

    PubMed  CAS  Google Scholar 

  26. Ryan SD, Britigan EM, Zasadil LM, Witte K, Audhya A, Roopra A, Weaver BA (2012) Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons. Proc Natl Acad Sci USA 109(33):E2205–E2214. doi:10.1073/pnas.1201911109

    Article  PubMed  CAS  Google Scholar 

  27. Chun AC, Jin DY (2003) Transcriptional regulation of mitotic checkpoint gene MAD1 by p53. J Biol Chem 278(39):37439–37450. doi:10.1074/jbc.M307185200

    Article  PubMed  CAS  Google Scholar 

  28. Iwanaga Y, Jeang KT (2002) Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. Cancer Res 62(9):2618–2624

    PubMed  CAS  Google Scholar 

  29. Kienitz A, Vogel C, Morales I, Muller R, Bastians H (2005) Partial downregulation of MAD1 causes spindle checkpoint inactivation and aneuploidy, but does not confer resistance towards taxol. Oncogene 24(26):4301–4310. doi:10.1038/sj.onc.1208589

    Article  PubMed  CAS  Google Scholar 

  30. Grabsch H, Takeno S, Parsons WJ, Pomjanski N, Boecking A, Gabbert HE, Mueller W (2003) Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer–association with tumour cell proliferation. J Pathol 200(1):16–22. doi:10.1002/path.1324

    Article  PubMed  CAS  Google Scholar 

  31. Cheung HW, Jin DY, Ling MT, Wong YC, Wang Q, Tsao SW, Wang X (2005) Mitotic arrest deficient 2 expression induces chemosensitization to a DNA-damaging agent, cisplatin, in nasopharyngeal carcinoma cells. Cancer Res 65(4):1450–1458. doi:10.1158/0008-5472.CAN-04-0567

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr. Shanshan Sun and Qingbin Song for assistance with immunohistochemistry staining analysis.

Conflict of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Breast Surgery, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China

    Qian Sun, Xianyu Zhang, Tong Liu, Yang Liu & Da Pang

  2. Department of Pathology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China

    Xiaolong Liu & Jingshu Geng

  3. Department of Medical Record, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China

    Xiaohui He

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  1. Qian Sun
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  2. Xianyu Zhang
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Correspondence to Da Pang.

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Sun, Q., Zhang, X., Liu, T. et al. Increased expression of Mitotic Arrest Deficient-Like 1 (MAD1L1) is associated with poor prognosis and insensitive to Taxol treatment in breast cancer. Breast Cancer Res Treat 140, 323–330 (2013). https://doi.org/10.1007/s10549-013-2633-8

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  • DOI: https://doi.org/10.1007/s10549-013-2633-8

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