Skip to main content

Advertisement

SpringerLink
Log in

HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case–control study

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

This case control study aims to investigate the role of HSP90 Gln488His (C > G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541–1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose–response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541–1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose–response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541–1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.

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

Similar content being viewed by others

References

  1. Fang DH, Fan CH, Ji Q, Qi BX, Li J, Wang L (2012) Differential effects of paraoxonase 1 (PON1) polymorphisms on cancer risk: evidence from 25 published studies. Mol Biol Rep 39:6801–6809

    Article  PubMed  CAS  Google Scholar 

  2. Zhang Y, Huang M, Zhu Z (2012) AIB1 polymorphisms with breast cancer susceptibility: a pooled analysis of variation in BRCA1/2 mutation carriers and non-carriers. Mol Biol Rep 39:6881–6886

    Article  PubMed  CAS  Google Scholar 

  3. He XF, Wei W, Li SX, Su J, Zhang Y, Ye XH, Liu Y, Wang W (2012) Association between the COMT Val158Met polymorphism and breast cancer risk: a meta-analysis of 30,199 cases and 38,922 controls. Mol Biol Rep 39(6):6811–6823

    Article  PubMed  CAS  Google Scholar 

  4. Economopoulos KP, Sergentanis TN (2010) Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis. Breast Cancer Res Treat 120:211–216

    Article  PubMed  Google Scholar 

  5. He BS, Pan YQ, Zhang Y, Xu YQ, Wang SK (2012) Effect of LEPR Gln223Arg polymorphism on breast cancer risk in different ethnic populations: a meta-analysis. Mol Biol Rep 39:3117–3122

    Article  PubMed  CAS  Google Scholar 

  6. Shen W, Cao X, Xi L, Deng L (2012) CXCL12 G801A polymorphism and breast cancer risk: a meta-analysis. Mol Biol Rep 39:2039–2044

    Article  PubMed  CAS  Google Scholar 

  7. Kampinga HH, Hageman J, Vos MJ et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111

    Article  PubMed  CAS  Google Scholar 

  8. Whitley D, Goldberg SP, Jordan WD (1999) Heat shock proteins: a review of the molecular chaperones. J Vasc Surg 29:748–751

    Article  PubMed  CAS  Google Scholar 

  9. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772

    Article  PubMed  CAS  Google Scholar 

  10. Passarino G, Cavalleri GL, Stecconi R et al (2003) Molecular Variation of Human HSP90a and HSP90b Genes in Caucasians. Human Mutation 21(5):554–555 (Mutation in Brief #612 Online)

    Article  PubMed  Google Scholar 

  11. MacLean MJ, Martinez-Llordella M, Bot N, Picard D (2005) A yeast-based assay reveals a functional defect of the Q488H polymorphism in human Hsp90α. Biochem Biophys Res Commun 337:133–137

    Article  PubMed  CAS  Google Scholar 

  12. Kobayakawa T, Yamada S, Mizuno A, Ohara-Nemoto Y, Baba TT, Nemoto TK (2009) Single nucleotide polymorphism that accompanies a missense mutation (Gln488His) impedes the dimerization of Hsp90. Protein J 28:24–28

    Article  PubMed  CAS  Google Scholar 

  13. Hatfield MP, Lovas S (2012) Role of Hsp70 in cancer growth and survival. Protein Pept Lett 19(6):616–624

    Article  PubMed  CAS  Google Scholar 

  14. Jalbout M, Bouaouina N, Gargouri J, Corbex M, Ben Ahmed S, Chouchane L (2003) Polymorphism of the stress protein HSP70-2 gene is associated with the susceptibility to the nasopharyngeal carcinoma. Cancer Lett 193:75–81

    Article  PubMed  CAS  Google Scholar 

  15. Tahara T, Shibata T, Arisawa T et al (2009) The BB genotype of heat-shock protein (HSP) 70-2 gene is associated with gastric pre-malignant condition in H. pylori-infected older patients. Anticancer Res 29:3453–3458

    PubMed  CAS  Google Scholar 

  16. Shibata T, Arisawa T, Tahara T et al (2009) Protective role of genetic polymorphism of heat shock protein 70-2 for gastric cancer risk. Dig Dis Sci 54:70–74

    Article  PubMed  CAS  Google Scholar 

  17. Kádár K, Kovács M, Karádi I et al (2008) Polymorphisms of TNF-alpha and LT-alpha genes in multiple myeloma. Leuk Res 32:1499–1504

    Article  PubMed  Google Scholar 

  18. Mestiri S, Bouaouina N, Ahmed SB et al (2001) Genetic variation in the tumor necrosis factor-alpha promoter region and in the stress protein hsp70-2: susceptibility and prognostic implications in breast carcinoma. Cancer 91:672–678

    Article  PubMed  CAS  Google Scholar 

  19. Bakkenist CJ, Koreth J, Williams CS, Hunt NC, McGee JO (1999) Heat shock cognate 70 mutations in sporadic breast carcinoma. Cancer Res 59:4219–4221

    PubMed  CAS  Google Scholar 

  20. Dworniczak B, Mirault ME (1987) Structure and expression of a human gene coding for a 71 kd heat shock ‘cognate’ protein. Nucleic Acids Res 15:5181–5197

    Article  PubMed  CAS  Google Scholar 

  21. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858

    Article  PubMed  CAS  Google Scholar 

  22. Bukau B, Deuerling E, Pfund C, Craig EA (2000) Getting newly synthesized proteins into shape. Cell 101:119–122

    Article  PubMed  CAS  Google Scholar 

  23. Rusin M, Zientek H, Krześniak M et al (2004) Intronic polymorphism (1541–1542delGT) of the constitutive heat shock protein 70 gene has functional significance and shows evidence of association with lung cancer risk. Mol Carcinog 39:155–163

    Article  PubMed  CAS  Google Scholar 

  24. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    Article  PubMed  CAS  Google Scholar 

  25. Neckers L, Ivy SP (2003) Heat shock protein 90. Curr Opin Oncol 15:419–424

    Article  PubMed  CAS  Google Scholar 

  26. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL (2007) RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell 25:207–217

    Article  PubMed  Google Scholar 

  27. Fu XS, Choi E, Bubley GJ, Balk SP (2005) Identification of hypoxia-inducible factor-1alpha (HIF-1alpha) polymorphism as a mutation in prostate cancer that prevents normoxia-induced degradation. Prostate 63:215–221

    Article  PubMed  CAS  Google Scholar 

  28. Zhao T, Lv J, Zhao J, Nzekebaloudou M (2009) Hypoxia-inducible factor-1alpha gene polymorphisms and cancer risk: a meta-analysis. J Exp Clin Cancer Res 28:159

    Article  PubMed  CAS  Google Scholar 

  29. Milner CM, Campbell RD (1992) Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics 36:357–362

    Article  PubMed  CAS  Google Scholar 

  30. Ollerenshaw M, Page T, Hammonds J, Demaine A (2004) Polymorphisms in the hypoxia inducible factor-1alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype. Cancer Genet Cytogenet 153:122–126

    Article  PubMed  CAS  Google Scholar 

  31. Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306

    Article  PubMed  Google Scholar 

  32. Rohlfs RV, Weir BS (2008) Distributions of Hardy–Weinberg equilibrium test statistics. Genetics 180:1609–1616

    Article  PubMed  CAS  Google Scholar 

  33. Modi S, Stopeck A, Linden H et al (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 17:5132–5139

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

A research grant has been received by HeSMO. FZ is receiving a research grant from HeSMO.

Conflict of interest

The authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, Athens, Greece

    Flora Zagouri, Irene Papaspyrou, Evaggelos Eleutherakis-Papaiakovou, Athanassios-Meletios Dimopoulos & Christos A. Papadimitriou

  2. 1st Propaedeutic Surgical Department, Hippocrateio Hospital, University of Athens, 114 Vas. Sofias av, 115 27, Athens, Greece

    Theodoros N. Sergentanis, Dimosthenis Chrysikos, George Theodoropoulos & George C. Zografos

  3. Department of Biology, University of Athens, Athens, Greece

    Maria Gazouli

  4. Department of Obstetrics and Gynaecology Alexandra Hospital, University of Athens, Athens, Greece

    Alexandra Tsigginou, Constantine Dimitrakakis & Aris Antsaklis

Authors
  1. Flora Zagouri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theodoros N. Sergentanis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Gazouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexandra Tsigginou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Constantine Dimitrakakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Irene Papaspyrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evaggelos Eleutherakis-Papaiakovou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimosthenis Chrysikos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. George Theodoropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. George C. Zografos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aris Antsaklis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Athanassios-Meletios Dimopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christos A. Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodoros N. Sergentanis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zagouri, F., Sergentanis, T.N., Gazouli, M. et al. HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case–control study. Mol Biol Rep 39, 10873–10879 (2012). https://doi.org/10.1007/s11033-012-1984-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-012-1984-2

Keywords

Search

Navigation