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

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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.

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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.

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Authors and Affiliations

  1. School of Chemical & Biotechnology, SASTRA University, Thanjavur, 613401, India

    Shaik Mohammad Naushad

  2. Center of Excellence in Biotechnology Research, King Saud University, PO Box 2455, Riyadh, 11451, Saudi Arabia

    Tajamul Hussain & Omar S. Al-Attas

  3. Department of Pathology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India

    Aruna Prayaga

  4. Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India

    Raghunadha Rao Digumarti

  5. Department of Surgical Oncology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India

    Suryanarayana Raju Gottumukkala

  6. Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India

    Vijay Kumar Kutala

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  1. Shaik Mohammad Naushad
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  2. Tajamul Hussain
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Correspondence to Vijay Kumar Kutala.

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Naushad, S.M., Hussain, T., Al-Attas, O.S. et al. Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes. Mol Cell Biochem 392, 273–280 (2014). https://doi.org/10.1007/s11010-014-2037-z

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  • DOI: https://doi.org/10.1007/s11010-014-2037-z

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