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Molecular and Cellular Biochemistry

, Volume 392, Issue 1–2, pp 273–280 | Cite as

Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes

  • Shaik Mohammad Naushad
  • Tajamul Hussain
  • Omar S. Al-Attas
  • Aruna Prayaga
  • Raghunadha Rao Digumarti
  • Suryanarayana Raju Gottumukkala
  • Vijay Kumar KutalaEmail author
Article

Abstract

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR–RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with “Luminal A” breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = −0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.

Keywords

Obesity Cytochrome P450 1A1 Catechol-O-methyl transferase Ras-association (RalGDS/AF-6) domain family member 1 Breast cancer type 1 susceptibility protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 Extracellular superoxide dismutase CpG island methylation 

Notes

Acknowledgments

This work was supported by the grant funded by Indian Council of Medical Research (ICMR), New Delhi (Ref No. 5/13/32/2007) and Prof. T. R. Rajagopalan Research Fund of SASTRA University, Thanjavur, India.

References

  1. 1.
    Jovanovic J, Rønneberg JA, Tost J et al (2010) The epigenetics of breast cancer. Mol Oncol 4(3):242–254PubMedCrossRefGoogle Scholar
  2. 2.
    Apostolou P, Fostira F (2013) Hereditary breast cancer: the era of new susceptibility genes. Biomed Res Int 2013:747318PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Simpson E, Brown KA (2013) Obesity and breast cancer: role of inflammation and aromatase. J Mol Endocrinol 51(3):T51–T59Google Scholar
  4. 4.
    Naushad SM, Pavani A, Digumarti RR et al (2011) Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. Mol Biol Rep 38(8):4893–4901PubMedCrossRefGoogle Scholar
  5. 5.
    Szymczak J, Milewicz A, Thijssen JH et al (1998) Concentration of sex steroids in adipose tissue after menopause. Steroids 63(5–6):319–321PubMedCrossRefGoogle Scholar
  6. 6.
    Naushad SM, Reddy CA, Rupasree Y et al (2011) Cross-talk between one-carbon metabolism and xenobiotic metabolism: implications on oxidative DNA damage and susceptibility to breast cancer. Cell Biochem Biophys 61(3):715–723PubMedCrossRefGoogle Scholar
  7. 7.
    Leung T, Rajendran R, Singh S, Garva R, Krstic-Demonacos M, Demonacos C (2013) Cytochrome P450 2E1 (CYP2E1) regulates the response to oxidative stress and migration of breast cancer cells. Breast Cancer Res 15(6):R107PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Perng W, Villamor E, Shroff MR et al (2013) Dietary intake, plasma homocysteine, and repetitive element DNA methylation in the Multi-Ethnic Study of Atherosclerosis (MESA). Nutr Metab Cardiovasc Dis S0939–4753(13):312–318Google Scholar
  9. 9.
    Fang Q, Yin J, Li F, Zhang J, Watford M (2010) Characterization of methionine adenosyltransferase 2beta gene expression in skeletal muscle and subcutaneous adipose tissue from obese and lean pigs. Mol Biol Rep 37(5):2517–2524PubMedCrossRefGoogle Scholar
  10. 10.
    Naushad SM, Reddy CA, Kumaraswami K et al (2014) Impact of hyperhomocysteinemia on breast cancer initiation and progression: epigenetic perspective. Cell Biochem Biophys 68(2):397–406PubMedCrossRefGoogle Scholar
  11. 11.
    Naushad SM, Prayaga A, Digumarti RR et al (2012) Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression is epigenetically regulated by one-carbon metabolism in invasive duct cell carcinoma of breast. Mol Cell Biochem 361(1–2):189–195PubMedCrossRefGoogle Scholar
  12. 12.
    Korah R, Healy JM, Kunstman JW et al (2013) Epigenetic silencing of RASSF1A deregulates cytoskeleton and promotes malignant behavior of adrenocortical carcinoma. Mol Cancer 12:87. doi: 10.1186/1476-4598-12-87 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ko E, Lee BB, Kim Y et al (2013) Association of RASSF1A and p63 with poor recurrence-free survival in node-negative stage I–II non-small cell lung cancer. Clin Cancer Res 19(5):1204–1212PubMedCrossRefGoogle Scholar
  14. 14.
    Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14(8):927–939PubMedCentralPubMedGoogle Scholar
  15. 15.
    Guo K, Searfoss G, Krolikowski D et al (2001) Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell Death Differ 8(4):367–376PubMedCrossRefGoogle Scholar
  16. 16.
    Naushad SM, Pavani A, Rupasree Y et al (2012) Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer. Mol Carcinog 51(Suppl 1):E32–E41PubMedCrossRefGoogle Scholar
  17. 17.
    Govindaiah V, Naushad SM, Prabhakara K, Krishna PC, Radha Rama Devi A (2009) Association of parental hyperhomocysteinemia and C677T methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem 42(4–5):380–386PubMedCrossRefGoogle Scholar
  18. 18.
    WHO (1995) Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 854:1–452Google Scholar
  19. 19.
    Mohammad NS, Yedluri R, Addepalli P, Gottumukkala SR, Digumarti RR, Kutala VK (2011) Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem 349(1–2):159–167PubMedCrossRefGoogle Scholar
  20. 20.
    Taioli E, Bradlow HL, Garbers SV et al (1999) Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk. Cancer Detect Prev 23(3):232–237PubMedCrossRefGoogle Scholar
  21. 21.
    Lachman HM, Morrow B, Shprintzen R et al (1996) Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet 67:468–472PubMedCrossRefGoogle Scholar
  22. 22.
    Lavigne JA, Goodman JE, Fonong T et al (2001) The effects of catechol-O-methyltransferase inhibition on estrogen metabolite and oxidative DNA damage levels in estradiol-treated MCF-7 cells. Cancer Res 61(20):7488–7494PubMedGoogle Scholar
  23. 23.
    Karbownik-Lewinska M, Szosland J, Kokoszko-Bilska A et al (2012) Direct contribution of obesity to oxidative damage to macromolecules. Neuro Endocrinol Lett 33(4):453–461PubMedGoogle Scholar
  24. 24.
    Biglia N, Peano E, Sgandurra P et al (2013) Body mass index (BMI) and breast cancer: impact on tumor histopathologic features, cancer subtypes and recurrence rate in pre and postmenopausal women. Gynecol Endocrinol 29(3):263–267PubMedCrossRefGoogle Scholar
  25. 25.
    Song Q, Huang R, Li J et al (2013) The diverse distribution of risk factors between breast cancer subtypes of ER, PR and HER2: a 10-year retrospective multi-center study in China. PLoS One 8(8):e72175PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Turkoz FP, Solak M, Petekkaya I et al (2013) The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women. J BUON 18(2):335–341PubMedGoogle Scholar
  27. 27.
    Adachi T, Inoue M, Hara H et al (2004) Relationship of plasma extracellular-superoxide dismutase level with insulin resistance in type 2 diabetic patients. J Endocrinol 181(3):413–417PubMedCrossRefGoogle Scholar
  28. 28.
    Peters I, Vaske B, Albrecht K et al (2007) Adiposity and age are statistically related to enhanced RASSF1A tumor suppressor gene promoter methylation in normal autopsy kidney tissue. Cancer Epidemiol Biomarkers Prev 16(12):2526–2532PubMedCrossRefGoogle Scholar
  29. 29.
    Ghosh S, Lu Y, Katz A, Hu Y, Li R (2007) Tumor suppressor BRCA1 inhibits a breast cancer-associated promoter of the aromatase gene (CYP19) in human adipose stromal cells. Am J Physiol Endocrinol Metab 292(1):E246–E252PubMedCrossRefGoogle Scholar
  30. 30.
    Tan EY, Campo L, Han C et al (2007) BNIP3 as a progression marker in primary human breast cancer; opposing functions in in situ versus invasive cancer. Clin Cancer Res 13(2 Pt 1):467–474PubMedCrossRefGoogle Scholar
  31. 31.
    Pajares B, Pollán M, Martín M et al (2013) Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis. Breast Cancer Res 15(6):R105PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Tao MH, Marian C, Nie J et al (2011) Body mass and DNA promoter methylation in breast tumors in the Western New York Exposures and Breast Cancer Study. Am J Clin Nutr 94(3):831–838PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Howard CB, Stevens J, Izevbigie EB, Walker A, McDaniel O (2003) Time and dose-dependent modulation of phase 1 and phase 2 gene expression in response to treatment of MCF-7 cells with a natural anti-cancer agent. Cell Mol Biol (Noisy-le-grand) 49(7):1057–1065Google Scholar
  34. 34.
    Mahadevan B, Arora V, Schild LJ et al (2006) Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology. Mol Carcinog 45(2):118–125PubMedCrossRefGoogle Scholar
  35. 35.
    Naushad SM, Krishnaprasad C, Devi AR (2014) Adaptive developmental plasticity in methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism limits its frequency in South Indians. Mol Biol Rep. doi: 10.1007/s11033-014-3163-0

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Shaik Mohammad Naushad
    • 1
  • Tajamul Hussain
    • 2
  • Omar S. Al-Attas
    • 2
  • Aruna Prayaga
    • 3
  • Raghunadha Rao Digumarti
    • 4
  • Suryanarayana Raju Gottumukkala
    • 5
  • Vijay Kumar Kutala
    • 6
    Email author
  1. 1.School of Chemical & BiotechnologySASTRA UniversityThanjavurIndia
  2. 2.Center of Excellence in Biotechnology ResearchKing Saud UniversityRiyadhSaudi Arabia
  3. 3.Department of PathologyNizam’s Institute of Medical SciencesHyderabadIndia
  4. 4.Department of Medical OncologyNizam’s Institute of Medical SciencesHyderabadIndia
  5. 5.Department of Surgical OncologyNizam’s Institute of Medical SciencesHyderabadIndia
  6. 6.Department of Clinical Pharmacology & TherapeuticsNizam’s Institute of Medical SciencesHyderabadIndia

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