Skip to main content

Advertisement

SpringerLink
Log in

A study on promoter methylation of PTEN in sporadic breast cancer patients from North India

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Epigenetic silencing of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) through DNA methylation has been implicated in the pathogenesis of breast cancer. Present study investigates the contribution of PTEN promoter methylation and its associated protein expression in sporadic breast cancer patients from North India.

Methods

A total of 360 paired breast carcinoma and adjacent normal tissue samples from 180 sporadic breast cancer patients were included in the present study and examined for PTEN promoter methylation status by methylation-specific polymerase chain reaction. Immunohistochemistry method was used for determining PTEN protein expression. Molecular findings were statistically correlated with various clinicopathological parameters to identify associations of clinical relevance.

Results

Presence of PTEN promoter methylation (39.44 %) significantly correlated with its expression downregulation (45.56 %) in breast tumors (P = 0.0001). Furthermore, their interaction with various clinical parameters was evidenced in stratified analysis. Correlation of PTEN promoter methylation with histologically more malignant grade and PTEN expression loss with triple negative tumor status remained significant even after Bonferroni correction (P < 0.003).

Conclusions

Results implicate promoter methylation to be a mechanism partially responsible for PTEN silencing in sporadic breast cancer for North Indian women. Besides, methylation and expression loss of PTEN exhibited promising potential as candidate biomarkers of risk assessment in subcategorized breast tumors with critical pathologic parameters.

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. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

    Article  PubMed  Google Scholar 

  2. Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer breast in India: a summary. Indian J Surg Oncol. 2010;1(1):8–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Takiar R, Srivastav A. Time trend in breast and cervix cancer of women in India—(1990–2003). Asian Pac J Cancer Prev. 2008;9(4):777–80.

    PubMed  Google Scholar 

  4. Wong NS, Anderson BO, Khoo KS, Ang PT, Yip CH, Lu YS, et al. Breast cancer in developing countries. Lancet. 2009;374(9701):1567.

    Article  Google Scholar 

  5. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science. 1997;275:1943–7.

    Article  CAS  PubMed  Google Scholar 

  6. Steck PA, Perhouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1 at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–62.

    Article  CAS  PubMed  Google Scholar 

  7. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–8.

    Article  CAS  PubMed  Google Scholar 

  8. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.

    Article  CAS  PubMed  Google Scholar 

  9. Lu Y, Lin YZ, LaPushin R, Cuevas B, Fang X, Yu SX, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene. 1999;25:7034–45.

    Article  Google Scholar 

  10. Stambolic V, Suzuki A, de la Pompa J, Brothers G, Mirtsos C, Sasaki T, et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998;95:29–39.

    Article  CAS  PubMed  Google Scholar 

  11. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 1998;280:1614–7.

    Article  CAS  PubMed  Google Scholar 

  12. Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, et al. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5-triphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci. 1999;96:6199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weng LP, Smith WM, Dahia PL, Ziebold U, Gil E, Lees JA, et al. PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res. 1999;59:5808–14.

    CAS  PubMed  Google Scholar 

  14. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13(5):283–96.

    CAS  PubMed  Google Scholar 

  15. Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell. 2008;133:403–14.

    Article  CAS  PubMed  Google Scholar 

  16. Singh B, Ittmann MM, Krolewski JJ. Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosom Cancer. 1998;21:166–71.

    Article  CAS  PubMed  Google Scholar 

  17. Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene. 1998;17:123–7.

    Article  CAS  PubMed  Google Scholar 

  18. Perren A, Weng LP, Boag AH, Ziebold U, Thakore K, Dahia PL, et al. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol. 1999;155:1253–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001;14:672–6.

    Article  CAS  PubMed  Google Scholar 

  20. Shi W, Zhang X, Pintilie M, Mai N, Miller N, Banerjee D, et al. Dysregulated PTEN-PKB and Negative receptor status in human breast cancer. Int J Cancer. 2003;104:195–203.

    Article  CAS  PubMed  Google Scholar 

  21. Sarah JR, Perks CM, Holly JMP, Bhoo-Pathy N, Looi LM, Mohammed NAT, et al. Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. Am J Clin Pathol. 2014;141:323–33.

    Article  Google Scholar 

  22. Chen ST, Yu SY, Tsai M, Yeh KT, Wang JC, Kao MC, et al. Mutation analysis of the putative tumor suppression gene PTEN/MMAC1 in sporadic breast cancer. Breast Cancer Res Treat. 1999;55:85–9.

    Article  CAS  PubMed  Google Scholar 

  23. Rhei E, Kang L, Bogomolinly F, Federici MG, Borgen PI, Boyd J. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in primary breast carcinomas. Cancer Res. 1997;57:3657–9.

    CAS  PubMed  Google Scholar 

  24. Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3(4):253–66.

    Article  CAS  PubMed  Google Scholar 

  25. Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5(1):37–50.

    Article  CAS  PubMed  Google Scholar 

  26. Khan S, Kumagai T, Vora J, Bose N, Sehgal I, Koeffler PH, et al. PTEN promoter is methylated in a proportion of invasive Breast cancers. Int J Cancer. 2004;112:407–10.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang HY, Liang F, Jia ZL, Song ST, Jiang ZF. PTEN mutation, methylation and expression in breast cancer patients. Oncol Lett. 2013;6:161–8.

    PubMed  PubMed Central  Google Scholar 

  28. García JM, Silva J, Pen C, Garcia V, Rodríguez R, Cruz MA, et al. Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosom Cancer. 2004;41:117–24.

    Article  PubMed  Google Scholar 

  29. Shetty PJ, Pasupuleti N, Chava S, Nasaruddin K, Hasan Q. Altered transcription and expression of PTEN in breast tumors: is it regulated by hypermethylation? Breast Dis. 2012;33:27–33.

    Article  Google Scholar 

  30. Salvesen HB, Macdonald N, Ryan A, Jacobs IJ, Lynch ED, Akslen LA, et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int J Cancer. 2001;91:22–6.

    Article  CAS  PubMed  Google Scholar 

  31. Rizvi MMA, Alam MS, Ali A, Mehdi SJ, Batra S, Mandal AK. Aberrant promoter methylation and inactivation of PTEN gene in cervical carcinoma from Indian population. J Cancer Res Clin Oncol. 2011;137:1255–62.

    Article  CAS  PubMed  Google Scholar 

  32. Zuberi M, Mir R, Dholariya S, Najar I, Yadav P, Javid J, et al. RASSF1 and PTEN promoter hypermethylation influences the outcome in epithelial ovarian cancer. Clin Ovarian Other Gynecol Cancer. 2014;7:33–9.

    Article  Google Scholar 

  33. Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004;64:3014–21.

    Article  CAS  PubMed  Google Scholar 

  34. Dahia PL, FitzGerald MG, Zhang X, Marsh DJ, Zheng Z, Pietsch T, et al. A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene. 1998;16:2403–6.

    Article  CAS  PubMed  Google Scholar 

  35. Zysman MA, Chapman WB, Bapat B. Considerations when analyzing the methylation status of PTEN tumor suppressor gene. Am J Pathol. 2002;160:795–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bertos NR, Park M. Breast cancer-one term, many entities? J Clin Invest. 2011;121(10):3789–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Polyak K. Heterogeneity in breast cancer. J Clin Invest. 2011;121(10):3786–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Turker MS. Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene. 2002;21:5388–93.

    Article  CAS  PubMed  Google Scholar 

  39. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.

    Article  CAS  PubMed  Google Scholar 

  40. Marty B, Maire V, Gravier E, Rigaill G, Vincent-Salomon A, Kappler M, et al. Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells. Breast Cancer Res. 2008;10(6):R101.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank all the patients who participated in this study and acknowledge the efforts and contribution of doctors, nurses, and hospital administration staff of AIIMS and all the support staff of Jamia Millia Islamia who made this study possible. Financial support for the production of the manuscript was provided by Council of Scientific and Industrial Research (CSIR), Delhi, India.

Author information

Authors and Affiliations

  1. Department of Biosciences, Jamia Millia Islamia, New Delhi, 110025, India

    Sarah Siddiqui, Naseem Akhter & Syed Akhtar Husain

  2. Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India

    S. V. S. Deo & N. K. Shukla

Authors
  1. Sarah Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naseem Akhter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. V. S. Deo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. K. Shukla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Syed Akhtar Husain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Syed Akhtar Husain.

Ethics declarations

Conflict of interest

None.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Siddiqui, S., Akhter, N., Deo, S.V.S. et al. A study on promoter methylation of PTEN in sporadic breast cancer patients from North India. Breast Cancer 23, 922–931 (2016). https://doi.org/10.1007/s12282-015-0665-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-015-0665-0

Keywords

Search

Navigation