Abstract
Synucleins are emerging as central players in the fundamental neural processes and in the formation of pathologically insoluble deposits characteristic of neurodegenerative diseases. However, synuclein γ (SNCG), previously identified as a breast cancer specific gene (BCSG1), is also highly expressed in breast carcinomas, but not expressed in normal or benign breast tissues. We analyzed SNCG gene expression in 93 clinical breast specimens and associated it with clinical outcome. Overall SNCG mRNA expression was detectable in 36% breast cancers. However, 81% of stage III/IV breast cancers were positive for SNCG expression, while only 15% of stage I/II breast cancers were positive for SNCG expression. In contrast, SNCG was undetectable in benign breast lesions. Expression of SNCG in the primary tumor also significantly associated with lymph node involvement and metastasis. There was no significant correlation between SNCG gene expression and age, menstruation, and status of ER, PR, PCNA, and HER-2. Patients whose tumors expressed SNCG had a significantly shorter DFS and a high probability of death when compared with those whose tumors did not express SNCG. The hazard ratio of metastasis or recurrence according to the SNCG status was 4.515 (95% CI, 1,188–17.154; P = 0.027). Cox multivariate analysis showed that SNCG had independent prognostic significance above and beyond conventional variables. This study suggests that the expression of SNCG is an independent predictive marker for recurrence and metastasis in breast cancer progression. SNCG is expected to be a useful marker for breast cancer progression and a potential target for breast cancer treatment.
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Abbreviations
- AD:
-
Alzheimer’s disease
- BCSG1:
-
breast cancer specific gene 1
- ER:
-
estrogen receptor
- DFS:
-
Disease-free survival
- PD:
-
Parkinson’s disease
- PR:
-
progesterone receptor
- SNCA:
-
α synuclein
- SNCB:
-
β synuclein
- SNCG:
-
γ synuclein
References
Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE (1997) Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 57:759–764
Xiao G, Liu YE, Gentz R, Sang QA, Ni J, Goldberg ID, Shi YE (1999) Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells. Proc Natl Acad Sci USA 96:3700–3705
Shi YE, Ni J, Xiao G, Liu YE, Fuchs A, Yu G, Su J, Cosgrove JM, Xing L, Zhang M, Li J, Aggarwal BB, Meager A, Gentz R (1997) Antitumor activity of the novel human breast cancer growth inhibitior, mammary-derived growth inhibitor-related gene, MRG. Cancer Res 57:3084–3091
Lavedan C, Leroy E, Dehejia A, Buchholtz S, Dutra A, Nussbaum RL, Polymeropoulos MH (1998) Identification, localization and characterization of the human gamma-synuclein gene. Hum Genet 103:106–112
Ninkina NN, Alimova-Kost MV, Paterson JW, Delaney L, Cohen BB, Imreh S, Gnuchev NV, Davies AM, Buchman VL (1998) Organization, expression and polymorphism of the human persyn gene. Hum Mol Genet 7:1417–1424
Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152:367–372
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286
Yoshimoto M, Iwai A, Kang D, Otero DA, Xia Y, Saitoh T (1995) NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci USA 92:9141–9145
Duda JE, Lee VM, Trojanowski JQ (2000) Neuropathology of synuclein aggregates. J Neurosci Res 61:121–127
Galvin JE, Uryu K, Lee VM, Trojanowski JQ (1999) Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc Natl Acad Sci USA 96:13450–13455
Jia T, Liu YE, Liu J, Shi YE (1999) Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res 59:742–747
Liu J, Spence MJ, Zhang YL, Jiang Y, Liu YE, Shi YE (2000) Transcriptional suppression of synuclein gamma (SNCG) expression in human breast cancer cells by the growth inhibitory cytokine oncostatin M. Breast Cancer Res Treat 62:99–107
Gupta A, Inaba S, Wong OK, Fang G, Liu J (2003) Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. Oncogene 22:7593–7599
Inaba S, Li C, Shi YE, Song DQ, Jiang JD, Liu J (2005) Synuclein gamma inhibits the mitotic checkpoint function and promotes chromosomal instability of breast cancer cells. Breast Cancer Res Treat 94:25–35
Jiang Y, Liu YE, Lu A, Gupta A, Goldberg ID, Liu J, Shi YE (2003) Stimulation of estrogen receptor signaling by gamma synuclein. Cancer Res 63:3899–3903
Jiang Y, Liu YE, Goldberg ID, Shi YE (2004) γ synuclein, a novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor α signaling and mammary tumorigenesis. Cancer Res 64:4539–4546
Lu A, Gupta A, Li C, Ahlborn TE, Ma Y, Shi YE, Liu J (2001) Molecular 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
Lu A, Zhang F, Gupta A, Liu J (2000) Blockade of AP1 transactivation abrogates the abnormal expression of breast cancer-specific gene 1 in breast cancer cells. J Biol Chem 277:31364–31372
Wu K, Weng Z, Tao Q, Lin G, Wu X, Qian H, Zhang Y, Ding X, Jiang Y, Shi YE (2003) Stage-specific expression of breast cancer-specific gene gamma synuclein. Cancer Epidemiol Biomarkers Prev 12:920–925
Bruening W, Giasson BI, Klein-Szanto AJ, Lee VM, Trojanowski JQ, Godwin AK (2000) Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer 88:2154–2163
Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J (2003) Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 63:664–673
Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK (2002) Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J Biol Chem 277:35050–35060
Mehra R, Varambally S, Ding L, Shen R, Sabel MS, Ghosh D, Chinnaiyan AM, Kleer CG (2005) Identification of GATA3 as a breast cancer prognostic marker by global gene expression Meta-analysis. Cancer Res 65:11259–11264
Arpino G, Weiss H, Lee AV, Schiff R, Placido SD, Osborne CK, Elledge RM (2005) Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97:1254–1261
Liu H, Liu W, Wu Y, Zhou Y, Xue R, Luo C, Wang L, Zhao W, Jiang JD, Liu J (2005) Loss of epigenetic control of synuclein-gamma gene as a molecular indicator of metastasis in a wide range of human cancers. Cancer Res 65:7635–7643
Li Z, Sclabas GM, Peng B, Hess KR, Abbruzzese JL, Evans DB, Chiao PJ (2004) Overexpression of synuclein-gamma in pancreatic adenocarcinoma. Cancer 101:58–65
Iwaki H, Kageyama S, Isono T, Wakabayashi Y, Okada Y, Yoshimura K, Terai A, Arai Y, Iwamura H, Kawakita M, Yoshiki T (2004) Diagnostic potential in bladder cancer of a panel of tumor markers (calreticulin, gamma -synuclein, and catechol-o-methyltransferase) identified by proteomic analysis. Cancer Sci 95:955–961
Acknowledgements
This study was supported in part by grant (99-028-01-CCE) from American cancer Society, and grant (DAMD17-01-1-0352) from the United States Army Medical Research and Development Command.
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Wu, K., Quan, Z., Weng, Z. et al. Expression of neuronal protein synuclein gamma gene as a novel marker for breast cancer prognosis. Breast Cancer Res Treat 101, 259–267 (2007). https://doi.org/10.1007/s10549-006-9296-7
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DOI: https://doi.org/10.1007/s10549-006-9296-7