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Tumor Biology

, Volume 35, Issue 3, pp 1847–1854 | Cite as

QM-FISH analysis of the genes involved in the G1/S checkpoint signaling pathway in triple-negative breast cancer

  • Sheng Zhang
  • Yingbo Shao
  • Guofang Hou
  • Jingchao Bai
  • Weiping Yuan
  • Linping Hu
  • Tao Cheng
  • Anders Zetterberg
  • Jin Zhang
Research Article

Abstract

This study was conducted to analyze copy number alterations (CNAs) of the genes involved in the G1/S checkpoint signaling pathway of triple-negative breast cancer (TNBC) and to evaluate their clinical value in the prognosis of TNBC. Quantitative multi-gene fluorescence in situ hybridization was used to study CNAs of the genes involved in the G1/S checkpoint signaling pathway, including cyclin d1 (CCND1), c-Myc, p21, cell-cycle-checkpoint kinase 2 gene, p16, retinoblastoma (Rb1), murine double minute 2 (Mdm2) and p53, in 60 TNBC samples and 60 non-TNBC samples. In comparison with the non-TNBC samples, CNAs of the genes involved in the G1/S checkpoint signaling pathway were more frequently observed in the TNBC samples (p = 0.000). Out of a total of eight genes, six (CCND1, c-Myc, p16, Rb1, Mdm2, and p53) exhibited significantly different CNAs between the TNBC group and the non-TNBC group. Univariate survival analysis revealed that the gene amplification of c-Myc (p = 0.008), Mdm2 (p = 0.020) and the gene deletion of p21 (p = 0.004), p16 (p = 0.015), and Rb1 (p = 0.028) were the independent predictive factor of 5-year OS for patients with TNBC. Cox multivariate analysis revealed that the gene amplification of c-Myc (p = 0.026) and the gene deletion of p21 (p = 0.019) and p16 (p = 0.034) were independent prognostic factors affecting the 5-year OS for TNBC. CNAs of the genes involved in the G1/S checkpoint signaling pathway presented a higher rate of incidence in TNBC than in non-TNBC, which could indicate one of the molecular mechanisms for the specific biological characteristics of TNBC. The genes c-Myc, p21, and p16 were correlated with the prognosis of TNBC and therefore may have potential clinical application values in the prognostic prediction of TNBC.

Keywords

Triple-negative breast cancer Copy number alterations Quantitative multi-gene fluorescence in situ hybridization 

Notes

Acknowledgments

This study was supported by International Cooperation, China Ministry of Science (No. 2010DFB30270).

Conflicts of interest

None

References

  1. 1.
    Ismail-Khan R, Bui MM. A review of triple-negative breast cancer. Cancer Control. 2010;17:173–6.PubMedGoogle Scholar
  2. 2.
    Griffiths CL, Olin JL. Triple negative breast cancer: a brief review of its characteristics and treatment options. J Pharm Pract. 2012;25:319–23.PubMedCrossRefGoogle Scholar
  3. 3.
    Ishikawa T, Shimizu D, Kito A, Ota I, Sasaki T, Tanabe M, et al. Breast cancer manifested by hematologic disorders. J Thorac Dis. 2012;4:650–4.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Ali SA. The hedgehog pathway in breast cancer. Chin J Cancer Res. 2012;24:261–2.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Woodson AH, Profato JL, Muse KI, Litton JK. Breast cancer in the young: role of the geneticist. J Thorac Dis. 2013;5 Suppl 1:S19–26.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Daemen A. An update on the genomic landscape of breast cancer: new opportunity for personalized therapy? Transl Cancer Res. 2012;1:279–82.Google Scholar
  7. 7.
    Nelson V, Rademaker A, Kaklamani V. Paradigm of polyendocrine therapy in endocrine responsive breast cancer: the role of fulvestrant. Chin Clin Oncol. 2013;2:10.Google Scholar
  8. 8.
    Nojima H. G1 and S-phase checkpoints, chromosome instability, and cancer. Methods Mol Biol. 2004;280:3–49.PubMedGoogle Scholar
  9. 9.
    Taylor BS, Barretina J, Socci ND, Decarolis P, Ladanyi M, Meyerson M, et al. Functional copy-number alterations in cancer. PLoS One. 2008;3:e3179.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Lu Y, Zhang X, Zhang J. Inhibition of breast tumor cell growth by ectopic expression of p16/INK4A via combined effects of cell cycle arrest, senescence and apoptotic induction, and angiogenesis inhibition. J Cancer. 2012;3:333–44.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Dirks PB, Rutka JT, Hubbard SL, Mondal S, Hamel PA. The E2F-family proteins induce distinct cell cycle regulatory factors in p16-arrested, U343 astrocytoma cells. Oncogene. 1998;17:867–76.PubMedCrossRefGoogle Scholar
  12. 12.
    Diccianni MB, Omura-Minamisawa M, Batova A, Le T, Bridgeman L, Yu AL. Frequent deregulation of p16 and the p16/G1 cell cycle-regulatory pathway in neuroblastoma. Int J Cancer. 1999;80:145–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Kovar H, Jug G, Aryee DN, Zoubek A, Ambros P, Gruber B, et al. Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors. Oncogene. 1997;15:2225–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011;18:333–45.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Ewen ME. Regulation of the cell cycle by the Rb tumor suppressor family. Results Probl Cell Differ. 1998;22:149–79.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen CY, Oliner JD, Zhan Q, Fornace Jr AJ, Vogelstein B, Kastan MB. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci U S A. 1994;91:2684–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Shangary S, Ding K, Qiu S, Nikolovska-Coleska Z, Bauer JA, Liu M, et al. Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer. Mol Cancer Ther. 2008;7:1533–42.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Joensuu K, Hagstrom J, Leidenius M, Haglund C, Andersson LC, Sariola H, et al. Bmi-1, c-myc, and Snail expression in primary breast cancers and their metastases—elevated Bmi-1 expression in late breast cancer relapses. Virchows Arch. 2011;459:31–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang H, Mannava S, Grachtchouk V, Zhuang D, Soengas MS, Gudkov AV, et al. c-Myc depletion inhibits proliferation of human tumor cells at various stages of the cell cycle. Oncogene. 2008;27:1905–15.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    McIntosh GG, Anderson JJ, Milton I, Steward M, Parr AH, Thomas MD, et al. Determination of the prognostic value of cyclin D1 overexpression in breast cancer. Oncogene. 1995;11:885–91.PubMedGoogle Scholar
  21. 21.
    Tobin NP, Sims AH, Lundgren KL, Lehn S, Landberg G. Cyclin D1, Id1 and EMT in breast cancer. BMC Cancer. 2011;11:417.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Lehn S, Tobin NP, Berglund P, Nilsson K, Sims AH, Jirstrom K, et al. Down-regulation of the oncogene cyclin D1 increases migratory capacity in breast cancer and is linked to unfavorable prognostic features. Am J Pathol. 2010;177:2886–97.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Reis-Filho JS, Savage K, Lambros MB, James M, Steele D, Jones RL, et al. Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis. Mod Pathol. 2006;19:999–1009.PubMedCrossRefGoogle Scholar
  24. 24.
    Lebeau A, Unholzer A, Amann G, Kronawitter M, Bauerfeind I, Sendelhofert A, et al. EGFR, HER-2/neu, cyclin D1, p21 and p53 in correlation to cell proliferation and steroid hormone receptor status in ductal carcinoma in situ of the breast. Breast Cancer Res Treat. 2003;79:187–98.PubMedCrossRefGoogle Scholar
  25. 25.
    Lundgren K, Brown M, Pineda S, Cuzick J, Salter J, Zabaglo L, et al. Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res. 2012;14:R57.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, et al. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res. 2004;64:8534–40.PubMedCrossRefGoogle Scholar
  27. 27.
    Choschzick M, Heilenkotter U, Lebeau A, Jaenicke F, Terracciano L, Bokemeyer C, et al. MDM2 amplification is an independent prognostic feature of node-negative, estrogen receptor-positive early-stage breast cancer. Cancer Biomark. 2010;8:53–60.PubMedGoogle Scholar
  28. 28.
    Somlo G, Chu P, Frankel P, Ye W, Groshen S, Doroshow JH, et al. Molecular profiling including epidermal growth factor receptor and p21 expression in high-risk breast cancer patients as indicators of outcome. Ann Oncol. 2008;19:1853–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Hui R, Macmillan RD, Kenny FS, Musgrove EA, Blamey RW, Nicholson RI, et al. INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis. Clin Cancer Res. 2000;6:2777–87.PubMedGoogle Scholar
  30. 30.
    Chano T, Ikebuchi K, Tomita Y, Jin Y, Inaji H, Ishitobi M, et al. RB1CC1 together with RB1 and p53 predicts long-term survival in Japanese breast cancer patients. PLoS One. 2010;5:e15737.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Sheng Zhang
    • 1
    • 2
    • 3
  • Yingbo Shao
    • 1
    • 2
    • 3
  • Guofang Hou
    • 1
    • 2
    • 3
  • Jingchao Bai
    • 1
    • 2
    • 3
  • Weiping Yuan
    • 4
    • 5
  • Linping Hu
    • 4
    • 5
  • Tao Cheng
    • 4
    • 5
  • Anders Zetterberg
    • 6
  • Jin Zhang
    • 1
    • 2
    • 3
    • 7
  1. 1.3rd Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research centerTianjin Medical University Cancer Institute and HospitalTianjinPeople’s Republic of China
  2. 2.Key Laboratory of Breast Cancer Prevention and Therapy of Ministry of EducationTianjinPeople’s Republic of China
  3. 3.Key Laboratory of Cancer Prevention and TherapyTianjinPeople’s Republic of China
  4. 4.Beijing Union Medical College Institute of Hematology and Blood Diseases HospitalChinese Academy of Medical SciencesTianjinPeople’s Republic of China
  5. 5.The State Key Laboratory of Experimental HematologyTianjinPeople’s Republic of China
  6. 6.Clinical Pathology Department of the Karolinska HospitalKarolinska InstituteSolnaSweden
  7. 7.3rd Department of Breast CancerTianjin Medical University Cancer HospitalTianjinPeople’s Republic of China

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