Skip to main content

Advertisement

SpringerLink
Log in

Influence of BCL2-938 C>A promoter polymorphism and BCL2 gene expression on the progression of breast cancer

  • Original Article
  • Published:
Tumor Biology

Abstract

BCL2 (B-cell leukemia/lymphoma 2) gene functions as antiapoptotic regulatory element and known to be associated with tumorigenesis. The SNP-938 (C>A) (rs2279115), located in the inhibitory P2 promoter of the BCL2 gene, influences differential binding affinities of transcriptional factors thereby affecting BCL2 expression. The present study is an attempt to evaluate the association between BCL2(-938C>A) polymorphism and clinical characteristics of breast cancer patients as well as to analyze BCL2 expression and Ki67 proliferation index with respect to the genotypes. One hundred ten primary breast cancer tumor tissues were genotyped for -938 C>A polymorphism through PCR-RFLP method as well as evaluated for BCL2 expression and ki67 proliferation index by immunohistochemistry. Evaluation of apoptosis level was performed by flowcytometry. The results revealed that AA genotype was associated with an increased risk (AA Vs AC + CC) by 2.86-fold (p = 0.07) for breast cancer development which reflected in elevated A allele frequency also. AA genotype was found to be predominant among BCL2 positive tumors as compared to BCL2 negative tumors. Further, AA genotype was found to be associated with advanced stage tumors, node positive status, and high Ki67 proliferation index compared to CA and CC genotypes indicating that elevated expression of BCL2 gene in the presence of A allele might be associated with decreased apoptosis and enhanced proliferation rate. AA genotype of BCL2-938C>A polymorphism might influence BCL2 gene expression there by associated with elevated risk for breast cancer progression. Probably, failure of apoptosis due to enhanced expression and antiapoptotic protein BCL2 might promote malignant growth.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Faderl S, Keating MJ, Do KA, Liang SY, Kantarjian HM, O’Brien S, et al. Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocyticleukemia (CLL). Leukemia. 2002;16(6):1045–52.

    Article  CAS  PubMed  Google Scholar 

  2. Keshgegian AA, Johnston E, Cnaan A. Bcl-2 oncoprotein positivity and high MIB-1 (Ki-67) proliferative rate are independent predictive markers for recurrence in prostate carcinoma. Am J Clin Pathol. 1998;110(4):443–9.

    Article  CAS  PubMed  Google Scholar 

  3. Ofner D, Riehemann K, Maier H, et al. Immunohistochemically detectable bcl-2 expression in colorectal carcinoma: correlation with tumor stage and patient survival. Br J Cancer. 1995;72:981–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Silvestrini R, Benini E, Veneroni S, Daidone MG, et al. p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients. J Clin Oncol. 1996;14(5):1604–10.

    Article  CAS  PubMed  Google Scholar 

  5. Seto M, Jaeger U, et al. Alternative promoter and exons, somatic mutation and deregulation of the Bcl-2 Ig fusion gene in lymphoma. EMBO J. 1988;7(1):123–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Young RL, Korsmeyer SJ. A negative regulatory element in the bcl-2 5′-untranslated region inhibits expression from an upstream promoter. Mol Cell Biol. 1993;13(6):3686–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bachmann HS, Heukamp LC, et al. Regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma. Int J Cancer. 2011;129(10):2390–9.

    Article  CAS  PubMed  Google Scholar 

  8. Cingeetham A, Vuree S, Dunna NR, Gorre M, Nanchari SR, Edathara PM, Meka P et al. Influence of BCL2 -938C > A and BAX-248G > A promoter polymorphisms in the development of AML: case-control study from South India. Tumor Biol. 2015;36(10): 7967–76.

  9. Li W, Qian C, et al. Association of BCL2-938C>A genetic polymorphism with glioma risk in Chinese Han population. Tumor Biol. 2014;35:2259–64.

    Article  CAS  Google Scholar 

  10. Lehnerdt GF, Franz P, Bankfalvi A, et al. The regulatory BCL2 promoter polymorphism (2938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma. Ann Oncol. 2009;20:1094–9.

    Article  CAS  PubMed  Google Scholar 

  11. Nuckel H, Frey UH et al. Association of a novel regulatory polymorphism (_938C_A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia. Blood. 2007;109(1):290–7.

  12. Bachmann HS, Otterbach F, Callies R, et al. The AA Genotype of the Regulatory BCL2 Promoter Polymorphism (-938C>A) Is Associated with a Favorable Outcome in Lymph Node-Negative Invasive Breast Cancer patients. Clin Cancer Res. 2007;13:5790–7.

    Article  CAS  PubMed  Google Scholar 

  13. Majid A, Tsoulakis O, Walewska R, et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 938A>C promoter single nucleotide polymorphism. Blood. 2008;111(2):874–7.

    Article  CAS  PubMed  Google Scholar 

  14. Pikor LA, Enfield KS, Cameron H, Lam WL. DNA extraction from paraffin embedded material for genetic and epigenetic analyses. J Vis Exp. 2011;49:2763.

    Google Scholar 

  15. Klintman M, Bendahl PO, Grabau D, Lovgren K, Malmstrom P, Ferno M. The prognostic value of Ki67 is dependent on estrogen receptor status and histological grade in premenopausal patients with node-negative breast cancer. Mod Pathol. 2010;23(2):251–9.

    Article  CAS  PubMed  Google Scholar 

  16. Kim OH, Jo HY, Lee J, Yoon SK. The C1772T genetic polymorphism in human HIF-1α gene associates with expression of HIF-1α protein in breast cancer. Oncol. Rep. 2008;20(5):1181–7.

  17. Meka PB, Cingeetham A, Nanchari SR, et al. HIF-1a (1772C>T) polymorphism as marker for breast cancer development. Tumor Biol. 2014;36:3215–20.

    Article  Google Scholar 

  18. Simoes-Wust AP, Schurpf T, Hall J, Stahel RA, Zangemeister-Wittke U. Bcl-2/bcl-xL bispecific antisense treatment sensitizes breast carcinoma cells to doxorubicin, paclitaxel and cyclophosphamide. Breast Cancer Res Treat. 2002;76(2):157–66.

    Article  PubMed  Google Scholar 

  19. Pepper C, Hooper K, et al. Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma. 2001;42(3):491–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank MNJ institute of oncology and regional cancer centre, Hyderabad, India for providing samples from breast cancer patients.

Author information

Authors and Affiliations

  1. Department of Genetics, Osmania University, Hyderabad, 500007, India

    Phanni bhushann Meka, Sarika Jarjapu, Santhoshi Rani Nanchari, Anuradha Cingeetham, Sandhya Annamaneni & Vishnupriya Satti

  2. Central Laboratory for Stem Cell Research & Translational Medicine, CLRD, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, India

    Sandeep Kumar Vishwakarma

  3. MNJ Institute of Oncology & Regional Cancer Centre, Hyderabad, India

    Srinivasulu Mukta & B. Triveni

Authors
  1. Phanni bhushann Meka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarika Jarjapu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandeep Kumar Vishwakarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Santhoshi Rani Nanchari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anuradha Cingeetham
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandhya Annamaneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Srinivasulu Mukta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B. Triveni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Vishnupriya Satti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vishnupriya Satti.

Ethics declarations

Conflicts of interest

None

Funding

This study was funded by University Grants Commission-Centre for Advanced Studies (UGC-CAS-II), New Delhi and DBT-OU-ISLARE. Phanni bhushann Meka is thankful to UGC-CAS-II for providing fellowship.

Additional information

Phanni bhushann Meka and Sarika Jarjapu are equal authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

bhushann Meka, P., Jarjapu, S., Vishwakarma, S.K. et al. Influence of BCL2-938 C>A promoter polymorphism and BCL2 gene expression on the progression of breast cancer. Tumor Biol. 37, 6905–6912 (2016). https://doi.org/10.1007/s13277-015-4554-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4554-0

Keywords

Search

Navigation