Skip to main content

Advertisement

SpringerLink
Log in

Synuclein Gamma Inhibits the Mitotic Checkpoint Function and Promotes Chromosomal Instability of Breast Cancer Cells

  • Report
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Summary

Aberrant expressions of the neuronal protein synuclein gamma (SNCG) in malignant mammary epithelial cells are strongly associated with the progression of breast cancer. SNCG is not expressed in normal breast tissues but abundantly expressed in a high percentage of invasive and metastatic breast carcinomas. Several studies have demonstrated that SNCG expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. To elucidate the molecular and cellular mechanisms underlying the tumorigenic functions of SNCG, we investigated the effects of SNCG expression on the mitotic checkpoint function of breast cancer cells. By conducting several different lines of investigations, we now demonstrate that SNCG expression in breast cancer cells overrides the mitotic checkpoint control and confers the cellular resistance to anti-microtubule drug-caused apoptosis. We further show that the inhibitory effects of SNCG on mitotic checkpoint can be overthrown by enforced overexpression of the mitotic checkpoint protein BubR1 in SNCG-expressing cells. These new findings combined with our previous observation that SNCG intracellularly associates with BubR1 together suggest that SNCG expression compromises the mitotic checkpoint control by inhibition of the normal function of BubR1, thereby promoting genetic instability. Genetic instability is recognized as an important contributing factor in tumorigenesis. Hence, our studies gain insight into the mechanisms whereby SNCG expression advances breast cancer disease progression and fasters tumor metastasis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

APC:

anaphase-promoting complex

Chx:

cycloheximide

ER:

estrogen receptor

FBS:

fetal bovine serum

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

IP:

immunoprecipitation

SNCG:

synuclein gamma

References

  1. H Ji Y Liu T Jia M Wang J Liu G Xiao B Joseph C Rosen Y Shi (1997) ArticleTitleIdentification of a breast cancer-specific gene, SNCG, by direct differential cDNA sequencing Cancer Res 57 759–764 Occurrence Handle9044857 Occurrence Handle1:CAS:528:DyaK2sXht1yrsrY%3D

    PubMed  CAS  Google Scholar 

  2. C Lavedan E Leroy A Dehejia S Buchholtz A Dutra R Nussbaum M Polymeropoulos (1998) ArticleTitleIdentification, localization characterization of the human γ-synuclein gene Human Genet 103 106–112 Occurrence Handle10.1007/s004390050792 Occurrence Handle1:CAS:528:DyaK1cXks12ht78%3D

    Article  CAS  Google Scholar 

  3. K Ueda H Fukushima E Masliah Y Xia A Iwai M Yoshimoto D Otero J Kondo Y Ihara T Saitoh (1993) ArticleTitleMolecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease Proc Natl Acad Sci USA 90 11282–11286 Occurrence Handle8248242 Occurrence Handle1:CAS:528:DyaK2cXitFCgsL4%3D

    PubMed  CAS  Google Scholar 

  4. Y Xia H Rohan Silva Particlede B Rosi L Yamaoka J Rimmler M Pericak-Vance A Roses X Chen E Masliah R DeTeresa A Iwai M Sundsmo R Thomas C Hofstetter E Gregory L Hansen R Katzman L Thal T Saitoh (1996) ArticleTitleGenetic studies in Alzheimer’s disease with a NACP/a-Synuclein polymorphism Ann Neurol 40 207–215 Occurrence Handle10.1002/ana.410400212 Occurrence Handle8773602 Occurrence Handle1:CAS:528:DyaK28XlsFSku7Y%3D

    Article  PubMed  CAS  Google Scholar 

  5. R Jakes M Spillantini M Goedert (1994) ArticleTitleIdentification of two distinct synucleins from human brain FEBS Lett 345 27–34 Occurrence Handle10.1016/0014-5793(94)00395-5 Occurrence Handle8194594 Occurrence Handle1:CAS:528:DyaK2cXlslehtb4%3D

    Article  PubMed  CAS  Google Scholar 

  6. W Bruening B Giasson J Klein-Szanto V Lee J Trojanowski A Godwin (2000) ArticleTitleSynucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary Cancer 88 2154–2163 Occurrence Handle10.1002/(SICI)1097-0142(20000501)88:9<2154::AID-CNCR23>3.0.CO;2-9 Occurrence Handle10813729 Occurrence Handle1:CAS:528:DC%2BD3cXjtF2mu7o%3D

    Article  PubMed  CAS  Google Scholar 

  7. K Wu Z Weng Q Tao G Lin X Wu H Qian Y Zhang X Ding Y Jiang YE Shi (2003) ArticleTitleStage-specific expression of breast cancer-specific gene γ-synuclein Cancer Epidemiol Biomarkers Prev 12 920–925 Occurrence Handle14504205 Occurrence Handle1:CAS:528:DC%2BD3sXnsValt7k%3D

    PubMed  CAS  Google Scholar 

  8. N Ninkina M Alimova-Kost J Paterson L Delaney B Cohen S Imreh N Gnuchev A Davies V Buchman (1998) ArticleTitleOrganization, expression polymorphism of the human persyn gene Hum Mol Genet 7 1417–1424 Occurrence Handle10.1093/hmg/7.9.1417 Occurrence Handle9700196 Occurrence Handle1:CAS:528:DyaK1cXmtVSlsbk%3D

    Article  PubMed  CAS  Google Scholar 

  9. A Lu A Gupta C Li TE Ahlborn Y Ma EY Shi J Liu (2001) ArticleTitleMolecular mechanisms for aberrant expression of the human breast cancer specific gene 1 in breast cancer cells: control of transcription by DNA methylation and intronic sequences Oncogene 20 5173–5185 Occurrence Handle10.1038/sj.onc.1204668 Occurrence Handle11526506 Occurrence Handle1:CAS:528:DC%2BD3MXmslGmu7g%3D

    Article  PubMed  CAS  Google Scholar 

  10. A Gupta AK Godwin L Vanderveer A Lu J Liu (2003) ArticleTitleHypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma Cancer Res 63 664–673 Occurrence Handle12566312 Occurrence Handle1:CAS:528:DC%2BD3sXosVyitQ%3D%3D

    PubMed  CAS  Google Scholar 

  11. T Jia Y Liu J Liu Y Shi (1999) ArticleTitleStimulation of breast cancer invasion and metastasis by breast cancer-specific synuclein (SNCG) Cancer Res 59 742–747 Occurrence Handle9973226 Occurrence Handle1:CAS:528:DyaK1MXhtFShsrs%3D

    PubMed  CAS  Google Scholar 

  12. A Gupta S Inaba OK Wong G Fang J Liu (2003) ArticleTitleBreast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1 Oncogene 22 7593–7599 Occurrence Handle10.1038/sj.onc.1206880 Occurrence Handle14576821 Occurrence Handle1:CAS:528:DC%2BD3sXotlaisr8%3D

    Article  PubMed  CAS  Google Scholar 

  13. SS Taylor E Ha F McKeon (1998) ArticleTitleThe human homologue of Bub3 is required for kinetochore locaklization of Bub1 and a Mad3/Bub1-related protein kinase J. Cell Biology 142 1–11 Occurrence Handle10.1083/jcb.142.1.1 Occurrence Handle1:CAS:528:DyaK1cXkslWhsL8%3D

    Article  CAS  Google Scholar 

  14. GKT Chan SA Jablonski JV Sudakin JC hittle TJ Yen (1999) ArticleTitleHuman BubR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC J Cell Biol 146 941–954 Occurrence Handle10.1083/jcb.146.5.941 Occurrence Handle10477750 Occurrence Handle1:CAS:528:DyaK1MXlvVKjsbs%3D

    Article  PubMed  CAS  Google Scholar 

  15. E Bergers PJV Diest JPA Baak (1996) ArticleTitleCell cycle analysis of 932 flow cytometric DNA histograms of fresh frozen breast carcinoma material Cancer 77 2258–2266 Occurrence Handle10.1002/(SICI)1097-0142(19960601)77:11<2258::AID-CNCR12>3.0.CO;2-W Occurrence Handle8635093 Occurrence Handle1:STN:280:BymB38vovFU%3D

    Article  PubMed  CAS  Google Scholar 

  16. S Tsutsui S Ohno S Murakami A Kataoka J Kinoshita Y Hachitanda (2002) ArticleTitleFlow cytometric analysis of DNA ploidy in primary, metastatic and recurrent breast cancers Oncol Rep 9 793–799 Occurrence Handle12066211 Occurrence Handle1:CAS:528:DC%2BD38XltlGrsro%3D

    PubMed  CAS  Google Scholar 

  17. DS Yoon RP Wersto W Zhou FJ Chrest ES Garrett TK Kwon E Gabrielson (2002) ArticleTitleVariable levels of chromosomal instability and mitotic spindle checkpoint defects in breast cancer Am J Pathol 161 391–397 Occurrence Handle12163363

    PubMed  Google Scholar 

  18. A Czuba D Lange E Chmielik K Woloszynska M Wojciechowska M Snietura J Liszka (2002) ArticleTitleDNA ploidy assessment method applied to primary breast carcinoma FNA biopsies Folia Histochem 40 105–106 Occurrence Handle1:CAS:528:DC%2BD38XlsFWiu7c%3D

    CAS  Google Scholar 

  19. K Baek H Shin J Yoo J Cho Y Choi Y Sung F McKeon (2003) ArticleTitleLee C p53 deficiency and defective mitotic checkpoint in proliferating T lymphocytes increase chromosomal instability through aberrant exit from mitotic arrest J Leukocyte Biol 73 850–861 Occurrence Handle10.1189/jlb.1202607 Occurrence Handle12773518 Occurrence Handle1:CAS:528:DC%2BD3sXksFegt7w%3D

    Article  PubMed  CAS  Google Scholar 

  20. SS Taylor D Hussein Y Wang S Elderkin CJ Morrow (2001) ArticleTitleKinetochore localization and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells J Cell Sci 114 4385–4395 Occurrence Handle11792804 Occurrence Handle1:CAS:528:DC%2BD38XnvFKmtQ%3D%3D

    PubMed  CAS  Google Scholar 

  21. Y Mao A Abrieu DW Cleveland (2003) ArticleTitleActivation and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1 Cell 114 87–98 Occurrence Handle10.1016/S0092-8674(03)00475-6 Occurrence Handle12859900 Occurrence Handle1:CAS:528:DC%2BD3sXlslWqtrw%3D

    Article  PubMed  CAS  Google Scholar 

  22. G Fang (2002) ArticleTitleCheckpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex Mol Biol Cell 13 755–766 Occurrence Handle10.1091/mbc.01-09-0437 Occurrence Handle11907259 Occurrence Handle1:CAS:528:DC%2BD38XivVeqtbk%3D

    Article  PubMed  CAS  Google Scholar 

  23. EA Harrington D Bebbington J Moore et al. (2004) ArticleTitleVX-680, a potent and selective small-molecule inhibitor of the aurora kinase, suppresses tumor growth in vivo Nat Med 10 262–267 Occurrence Handle10.1038/nm1003 Occurrence Handle14981513 Occurrence Handle1:CAS:528:DC%2BD2cXhs1Wnur4%3D

    Article  PubMed  CAS  Google Scholar 

  24. HJ Shin KH Baek AH Jeon et al. (2003) ArticleTitleDual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability Cancer cell 4 483–497 Occurrence Handle10.1016/S1535-6108(03)00302-7 Occurrence Handle14706340 Occurrence Handle1:CAS:528:DC%2BD2cXitFOjtg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  25. SS Taylor F McKeon (1997) ArticleTitleKinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage Cell 89 727–735 Occurrence Handle10.1016/S0092-8674(00)80255-X Occurrence Handle9182760 Occurrence Handle1:CAS:528:DyaK2sXjs1ejsL8%3D

    Article  PubMed  CAS  Google Scholar 

  26. A Musuio C Montagna D Zambroni E Indino O Barbieri L Citti A Villa T Ried P Vezzoni (2003) ArticleTitleInhibition of Bub1 results in genomic instability and anchorage-independent growth of normal human fibroblasts Cancer Res 63 2855–2863 Occurrence Handle12782591

    PubMed  Google Scholar 

  27. JN Li DQ Song YH Lin QY Hu L Yin G Bekesi JF Holland J Jiang (2003) ArticleTitleInhibition of microtubule polymerization by 3-bromopropionylamino benzoylurea (JIMB01), a new cancericidal tubulin ligand Biochem Pharmacol 65 1691–1699 Occurrence Handle10.1016/S0006-2952(03)00101-1 Occurrence Handle12754105 Occurrence Handle1:CAS:528:DC%2BD3sXjs1Cqt70%3D

    Article  PubMed  CAS  Google Scholar 

  28. T Karlsson Hen R Henriksson H Hedman (2003) ArticleTitleInduction of apoptosis in resistant glioma cells by synthetic caspase-activation J Neurooncol 66 71–79 Occurrence Handle10.1023/B:NEON.0000013485.09953.25

    Article  Google Scholar 

  29. T Sudo M Nitta H Saya NT Ueno (2004) ArticleTitleDependence of paclitaxel sensitivity on a functional spindle assembly checkpoint Cancer Res 64 2502–2508 Occurrence Handle10.1158/0008-5472.CAN-03-2013 Occurrence Handle15059905 Occurrence Handle1:CAS:528:DC%2BD2cXis1yjtbc%3D

    Article  PubMed  CAS  Google Scholar 

  30. GKT Chan BT Schaar TJ Yen (1998) ArticleTitleCharacterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F and BubR1 J Cell Biol 143 49–63 Occurrence Handle10.1083/jcb.143.1.49 Occurrence Handle9763420 Occurrence Handle1:CAS:528:DyaK1cXmsFaltr4%3D

    Article  PubMed  CAS  Google Scholar 

  31. S Tsutsui S Ohno S Murakami Y Hachitanda S Oda (2002) ArticleTitleDNA, aneuploidy in relation to the combination of analysis of estrogen receptor, progesterone receptor, p53 protein and epidermal growth factor receptor in 498 breast cancers Oncology 63 48–55 Occurrence Handle10.1159/000065720 Occurrence Handle12187071 Occurrence Handle1:CAS:528:DC%2BD38XmtlGiurw%3D

    Article  PubMed  CAS  Google Scholar 

  32. M Shichiri K Yoshinaga H Hisatomi K Sugihara Y Hirata (2002) ArticleTitleGenetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival Cancer Res 62 13–17 Occurrence Handle11782350 Occurrence Handle1:CAS:528:DC%2BD38XntVyqtw%3D%3D

    PubMed  CAS  Google Scholar 

  33. B Ouyang JA Knauf K Ain B Nacev JA Fagin (2002) ArticleTitleMechanisms of aneuploidy in thyroid cancer cell lines and tissues: evidence for mitotic checkpoint dysfunction without mutations in BUB1 and BUBR1 Clin Endocrinol 56 341–350 Occurrence Handle10.1046/j.1365-2265.2002.01475.x Occurrence Handle1:CAS:528:DC%2BD38XjtlKhtb8%3D

    Article  CAS  Google Scholar 

  34. JA Fagin (2002) ArticleTitleMinireview: brandes from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid Mol Endocrinol 16 903–911 Occurrence Handle10.1210/me.16.5.903 Occurrence Handle11981026 Occurrence Handle1:CAS:528:DC%2BD38XjsFGhs7o%3D

    Article  PubMed  CAS  Google Scholar 

  35. KA Myrie MJ Percy JN Azim CK Neeley EM Petty (2000) ArticleTitleMutation and expression analysais of human BUB1 and BUB1B in aneuploid breast cancer cell lines Cancer Lett 152 193–199 Occurrence Handle10.1016/S0304-3835(00)00340-2 Occurrence Handle10773412 Occurrence Handle1:CAS:528:DC%2BD3cXisFGmtLk%3D

    Article  PubMed  CAS  Google Scholar 

  36. DP Cahill C Lengauer J Yu GJ Riggins JK Willson SD Markowitz KW Kinzler B Vogelstein (1998) ArticleTitleMutations of mitotic checkpoint genes in human cancers Nature 392 300–303 Occurrence Handle10.1038/32688 Occurrence Handle9521327 Occurrence Handle1:CAS:528:DyaK1cXitFahsro%3D

    Article  PubMed  CAS  Google Scholar 

  37. Y Imai Y Shiratori N Kato T Inoue M Omata (1999) ArticleTitleMutational inactivation of mitotic checkpoint genes, hsMAD2 and hBUB1, is rare in sporadic digestive tract cancers Jpn J Cancer Res 90 837–840 Occurrence Handle10543255 Occurrence Handle1:CAS:528:DyaK1MXmt1GqsLk%3D

    PubMed  CAS  Google Scholar 

  38. GF Jiang A Liu J Liu Y Shi (2003) ArticleTitleSynuclein gamma, a novel Hsp70 binding protein, stimulates ligand-dependent estrogen receptor signaling in breast cancer Cancer Res 63 3899–3903 Occurrence Handle12873981 Occurrence Handle1:CAS:528:DC%2BD3sXlsFOjtb8%3D

    PubMed  CAS  Google Scholar 

  39. Jiang (2004) ArticleTitleStimulation of estrogen receptor signaling by gamma synuclein Cancer Res 64 4539–4546 Occurrence Handle10.1158/0008-5472.CAN-03-3650 Occurrence Handle15231664 Occurrence Handle1:CAS:528:DC%2BD2cXltlOrsLc%3D

    Article  PubMed  CAS  Google Scholar 

  40. Pan (2002) ArticleTitleGodwin AK γ -Synuclein promotes cancer cell survial and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK, pathways J Biol Chem 277 35050–35060 Occurrence Handle10.1074/jbc.M201650200 Occurrence Handle12121974 Occurrence Handle1:CAS:528:DC%2BD38Xnt1Wgtrg%3D

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. VA Palo Alto Health Care System, Palo Alto, CA, USA

    Satoru Inaba, Cong Li & Jingwen Liu

  2. Long Island Jewish Medical Center, New Hyde Park, NY, USA

    Y. Eric Shi

  3. Institute of Medicinal Biotechnology, Chinese Academy of Medicinal Sciences, Beijing, China

    Dan-Qing Song & Jian-Dong Jiang

Authors
  1. Satoru Inaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y. Eric Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dan-Qing Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Dong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jingwen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jingwen Liu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inaba, S., Li, C., Shi, Y.E. et al. Synuclein Gamma Inhibits the Mitotic Checkpoint Function and Promotes Chromosomal Instability of Breast Cancer Cells. Breast Cancer Res Treat 94, 25–35 (2005). https://doi.org/10.1007/s10549-005-6938-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-005-6938-0

Key words

Search

Navigation