Abstract
Background
Functional variants of the xenobiotic-metabolizing genes (XMG) might modulate breast cancer (BC) risk by altering the rate of metabolism and clearance of myriad types of potent carcinogens from the breast tissue. Despite mounting evidence on the role of XMG variants on BC risk, the current knowledge regarding their influence on BC development is still fragmentary.
Methods
The present study examined the candidate genetic variants in CYP1A1, NQO1, GST-T1, GST-M1, and GST-P1 in 1002 subjects (502 BC patients and 500 disease-free women). PCR–RFLP was employed to genotype the mono-nucleotide variation in CYP1A1, NQO1, and GST-P1, and allele-specific PCR was used to detect the deletion polymorphism in GST-T1 and GST-M1 genes.
Results
Regarding CYP1A1-M1 polymorphism, the heterozygous TC and mutant CC genotype conferred 1.47-fold (95% CI 1.13–1.91, p = 0.004) and 1.84-fold (95% CI 1.17–2.91, p = 0.009) elevated risk of BC. GST-T1 null genotype was associated with increased BC risk (OR 1.47; 95% CI 1.02–2.11, p = 0.037). For the NQO1 C609T variant, the mutant T allele was associated with BC risk with an odds ratio of 1.22 (95% CI 1.02–1.48, p = 0.034). Combinatorial analysis indicated that the presence of NQO1*2 (CT), CYP1A1-M1 (CC), and GST-P1 rs1695 (AG) genotypes conferred 16.7-fold elevated risk of BC (95% CI 3.65–76.85; p < 0.001). Moreover, GST-M1 null genotype was associated with the development of larger primary breast tumors.
Conclusion
Xenobiotic-metabolizing gene polymorphisms may play a crucial role in mammary carcinogenesis in South Indian women.
Similar content being viewed by others
References
Azamjah N, Soltan-Zadeh Y, Zayeri F (2019) Global trend of breast cancer mortality rate: a 25-year study. Asian Pac J Cancer Prev 20:2015–2020
Malvia S, Bagadi SA, Dubey US, Saxena S (2017) Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol 13:289–295
Andersen ZJ, Stafoggia M, Weinmayr G et al (2017) Long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in 15 European cohorts within the ESCAPE project. Environ Health Perspect 13:107005
Eldakroory SA, Morsi DE, Abdel-Rahman RH et al (2017) Correlation between toxic organochlorine pesticides and breast cancer. Hum Exp Toxicol 36:1326–1334
Russo J, Russo IH (2006) The role of estrogen in the initiation of breast cancer. J Steroid Biochem Mol Biol 102:89–96
Nimrod A, Ryan KJ (1975) Aromatization of androgens by human abdominal and breast fat tissue. J Clin Endocrinol Metab 40:367–372
Jefcoate CR, Liehr JG, Santen RJ et al (2000) Tissue-specific synthesis and oxidative metabolism of estrogens. J Natl Cancer Inst Monogr 25:95–112
Parkinson A, Ogilvie BW, Buckley DB et al (2001) Biotransformation of xenobiotics. In: Klaassen CD (ed) Casarett and Doull’s toxicology: the basic science of poisons, 6th edn. McGraw-Hill Medical, New York, pp 133–224
Murray GI, Patimalla S, Stewart KN et al (2010) Profiling the expression of cytochrome P450 in breast cancer. Histopathology 57:202–211
Vinothini G, Nagini S (2010) Correlation of xenobiotic-metabolizing enzymes, oxidative stress and NFkappaB signaling with histological grade and menopausal status in patients with adenocarcinoma of the breast. Clin Chim Acta 411:368–374
Roy AK, Upadhyaya P, Evans FE, El-Bayoumy K (1991) Structural characterization of the major adducts formed by reaction of 4,5- epoxy-4,5-dihydro-1-nitropyrene with DNA. Carcinogenesis 12:577–581
Raftogianis R, Creveling C, Weinshilboum R, Weisz J (2000) Estrogen metabolism by conjugation. J Natl Cancer Inst Monogr 27:113–124
Cavalieri E, Frenkel K, Liehr JG et al (2000) Estrogens as endogenous genotoxic agents—DNA adducts and mutations. J Natl Cancer Inst Monogr 27:75–93
Kawajiri K, Nakachi K, Imai K et al (1990) Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450IA1 gene. FEBS Lett 263:131–133
Hefler LA, Tempfer CB, Grimm C et al (2004) Estrogen-metabolizing gene polymorphisms in the assessment of breast carcinoma risk and fibroadenoma risk in Caucasian women. Cancer 101:264–269
Sergentanis TN, Economopoulos KP (2010a) Four polymorphisms in cytochrome P450 1A1 (CYP1A1) gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 122:459–469
Benson AM (1980) Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci USA 77:5216–5220
Larson RA (1999) Prevalence of the inactivating 609CT polymorphism in the NAD(P)H: quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. Blood 94:803–807
Kim DW, Cho JY (2018) NQO1 is required for β-lapachone-mediated downregulation of breast-cancer stem-cell activity. Int J Mol Sci 19:3813
Siegel D, McGuinness SM, Winski SL, Ross D (1999) Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics 9:113–121
Yang Y, Zhang Y, Wu Q et al (2014) Clinical implications of high NQO1 expression in breast cancers. J Exp Clin Cancer Res 33:14
Dirven HA, van Ommen B, van Bladeren PJ (1994) Involvement of human glutathione S-transferase isoenzymes in the conjugation of cyclophosphamide metabolites with glutathione. Cancer Res 54:6215–6220
Seidegård J, Vorachek WR, Pero RW, Pearson WR (1988) Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proc Natl Acad Sci USA 85:7293–7297
Pemble S, Schroeder KR, Spencer SR, Meyer DJ et al (1994) Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J 300:271–276
Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600
Harries LW, Stubbins MJ, Forman D et al (1997) Identification of genetic polymorphisms at the glutathione S-transferase Pi locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis 18:641–644
Sweeney C, McClure GY, Fares MY et al (2000) Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism. Cancer Res 60:5621–5624
Zhang BL, Sun T, Zhang BN et al (2011) Polymorphisms of GSTP1 is associated with differences of chemotherapy response and toxicity in breast cancer. Chin Med J 124:199–204
Rajagopal T, Seshachalam A, Rathnam KK et al (2020) DNA repair genes hOGG1, XRCC1 and ERCC2 polymorphisms and their molecular mapping in breast cancer patients from India. Mol Biol Rep 47:5081–5090
Naif HM, Al-Obaide M, Hassani HH et al (2018) Association of cytochrome CYP1A1 gene polymorphisms and tobacco smoking with the risk of breast cancer in women from Iraq. Front Public Health 6:96
Kiruthiga PV, Kannan MR, Saraswathi C et al (2011) CYP1A1 gene polymorphisms: lack of association with breast cancer susceptibility in the southern region (Madurai) of India. Asian Pac J Cancer Prev 12:2133–2138
Syamala VS, Sreeja L, Syamala V et al (2008) Influence of germline polymorphisms of GSTT1, GSTM1, and GSTP1 in familial versus sporadic breast cancer susceptibility and survival. Fam Cancer 7:213–220
Saxena A, Dhillon VS, Raish M et al (2009) Detection and relevance of germline genetic polymorphisms in glutathione S-transferases (GSTs) in breast cancer patients from northern Indian population. Breast Cancer Res Treat 115:537–543
Kalacas NA, Garcia JA, Sy Ortin T et al (2019) GSTM1 and GSTT1 genetic polymorphisms and breast cancer risk in selected Filipino cases. Asian Pac J Cancer Prev 2:529–535
Ritchie MD, Hahn LW, Roodi N et al (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 69:138–147
Belle DJ, Singh H (2008) Genetic factors in drug metabolism. Am Fam Phys 77:1553–1560
Chacko P, Joseph T, Mathew BS et al (2005) Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome. Mutat Res 581:153–163
Shen Y, Li DK, Wu J et al (2006) Joint effects of the CYP1A1 MspI, ERalpha PvuII, and ERalpha XbaI polymorphisms on the risk of breast cancer: results from a population-based case-control study in Shanghai, China. Cancer Epidemiol Biomark Prev 15:342–347
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 61:715–723
Syamala VS, Syamala V, Sheeja VR et al (2010) Possible risk modification by polymorphisms of estrogen metabolizing genes in familial breast cancer susceptibility in an Indian population. Cancer Invest 28:304–311
Cotterchio M, Mirea L, Ozcelik H, Kreiger N (2014) Active cigarette smoking, variants in carcinogen metabolism genes and breast cancer risk among pre- and postmenopausal women in Ontario, Canada. Breast J 20:468–480
Singh N, Mitra AK, Garg VK et al (2007) Association of CYP1A1 polymorphisms with breast cancer in North Indian women. Oncol Res 16:587–597
Miyoshi Y, Takahashi Y, Egawa C, Noguchi S (2002) Breast cancer risk associated with CYP1A1 genetic polymorphisms in Japanese women. Breast J 8:209–215
Oliveira CB, Cardoso-Filho C, Bossi LS et al (2015) Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. Clinics 70:680–685
Singh V, Rastogi N, Sinha A et al (2007) A study on the association of cytochrome-P450 1A1 polymorphism and breast cancer risk in north Indian women. Breast Cancer Res Treat 101:73–81
Rebbeck TR (1997) Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomark Prev 6:733–743
Zheng T, Holford TR, Zahm SH et al (2003) Glutathione S-transferase M1 and T1 genetic polymorphisms, alcohol consumption and breast cancer risk. Br J Cancer 88:58–62
Park SK, Yim DS, Yoon KS et al (2004) Combined effect of GSTM1, GSTT1, and COMT genotypes in individual breast cancer risk. Breast Cancer Res Treat 88:55–62
Park SK, Yoo KY, Lee SJ et al (2000) Alcohol consumption, glutathione S-transferase M1 and T1 genetic polymorphisms and breast cancer risk. Pharmacogenetics 10:301–309
Spurdle AB, Chang JH, Byrnes GB et al (2007) A systematic approach to analysing gene-gene interactions: polymorphisms at the microsomal epoxide hydrolase EPHX and glutathione S-transferase GSTM1, GSTT1, and GSTP1 loci and breast cancer risk. Cancer Epidemiol Biomark Prev 16:769–774
Curran JE, Weinstein SR, Griffiths LR (2000) Polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and breast cancer susceptibility. Cancer Lett 153:113–120
Jaramillo-Rangel G, Ortega-Martínez M, Cerda-Flores RM, Barrera-Saldaña HA (2015) Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico. Genet Mol Res 14:6465–6471
Hashemi M, Eskandari-Nasab E, Fazaeli A et al (2012) Association between polymorphisms of glutathione S-transferase genes (GSTM1, GSTP1 and GSTT1) and breast cancer risk in a sample Iranian population. Biomark Med 6:797–803
Sergentanis TN, Economopoulos KP (2010b) GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121:195–202
Samson M, Swaminathan R, Rama R et al (2007) Role of GSTM1 (Null/Present), GSTP1 (Ile105Val) and P53 (Arg72Pro) genetic polymorphisms and the risk of breast cancer: a case control study from South India. Asian Pac J Cancer Prev 8:253–257
Unlü A, Ates NA, Tamer L, Ates C (2008) Relation of glutathione S-transferase T1, M1 and P1 genotypes and breast cancer risk. Cell Biochem Funct 26:643–647
Lizard-Nacol S, Coudert B, Colosetti P et al (1999) Glutathione S-transferase M1 null genotype: lack of association with tumour characteristics and survival in advanced breast cancer. Breast Cancer Res 1:81–87
Mitrunen K, Jourenkova N, Kataja V et al (2001) Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer. Cancer Epidemiol Biomark Prev 10:229–236
Millikan R, Pittman G, Tse CK et al (2000) Glutathione S-transferases M1, T1, and P1 and breast cancer. Cancer Epidemiol Biomark Prev 9:567–573
Al-Eitan LN, Rababa’h DM, Alghamdi MA, Khasawneh RH (2019) Association of GSTM1, GSTT1 and GSTP1 polymorphisms with breast cancer among Jordanian women. Onco Targets Ther 12:7757–7765
Helzlsouer KJ, Selmin O, Huang H et al (1998) Association between glutathione S-transferase M1, P1, and T1 genetic polymorphisms and development of breast cancer. J Natl Cancer Inst 90:512–518
Sundberg K, Johansson AS, Stenberg G et al (1998) Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1–1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons. Carcinogenesis 19:433–436
Ma J, Zhu SL, Liu Y et al (2017) GSTP1 polymorphism predicts treatment outcome and toxicities for breast cancer. Oncotarget 8:72939–72949
Miao LF, Ye XH, He XF (2020) Individual and combined effects of GSTM1, GSTT1, and GSTP1 polymorphisms on breast cancer risk: a meta-analysis and re-analysis of systematic meta-analyses. PLoS ONE 15:e0216147
Siegel D, Yan C, Ross D (2012) NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83:1033–1040
Yadav P, Mir R, Nandi K et al (2016) The C609T (Pro187Ser) null polymorphism of the NQO1 gene contributes significantly to breast cancer susceptibility in North Indian populations: a case control study. Asian Pac J Cancer Prev 17:1215–1219
Sarmanová J, Sůsová S, Gut I et al (2004) Breast cancer: role of polymorphisms in biotransformation enzymes. Eur J Hum Genet 12:848–854
Menzel HJ, Sarmanova J, Soucek P et al (2004) Association of NQO1 polymorphism with spontaneous breast cancer in two independent populations. Br J Cancer 90:1989–1994
Santos SS, Ortega Jácome G, Koifman R, Koifman S (2013) CYP17, CYP19, and NQO1 genetic polymorphisms and breast cancer susceptibility in young women in Brazil. JAMMR 4:68–80
Fagerholm R, Hofstetter B, Tommiska J et al (2008) NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer. Nat Genet 40:844–853
Jamieson D, Cresti N, Bray J et al (2011) Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy. Pharmacogenet Genomics 21:808–819
Chaturvedi P, Tulsyan S, Agarwal G et al (2015) Relationship of MTHFR and NQO1 pharmacogenetics and chemotherapy clinical outcomes in breast cancer patients. Biochem Genet 53:211–222
Singh V, Upadhyay G, Rastogi N et al (2011) Polymorphism of xenobiotic-metabolizing genes and breast cancer susceptibility in North Indian women. Genet Test Mol Biomark 15:343–349
Siegelmann-Danieli N, Buetow KH (2002) Significance of genetic variation at the glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase 1 detoxification genes in breast cancer development. Oncology 62:39–45
Peng Q, Lu Y, Lao X et al (2014) The NQO1 Pro187Ser polymorphism and breast cancer susceptibility: evidence from an updated meta-analysis. Diagn Pathol 9:100
Lajin B, Alachkar A (2013) The NQO1 polymorphism C609T (Pro187Ser) and cancer susceptibility: a comprehensive meta-analysis. Br J Cancer 109:1325–1337
Sakoda LC, Blackston CR, Xue K et al (2008) Glutathione S-transferase M1 and P1 polymorphisms and risk of breast cancer and fibrocystic breast conditions in Chinese women. Breast Cancer Res Treat 109:143–155
Acknowledgements
The authors express their deep gratitude to all the study participants who volunteered in the study and the medical staff of Dr. G.V.N Cancer Institute and MMHRC. The authors also thank SASTRA – Deemed University for infrastructural support.
Funding
This study was funded by the Department of Science and Technology, SERB – Government of India (YSS/2015/001692).
Author information
Authors and Affiliations
Contributions
TR: Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, and Writing—review & editing. AS: Methodology, Resources, and Supervision. KKR: Methodology and Resources. ST: Investigation, Supervision, and Writing—review & editing. AJ: Validation and Software. SV: Conceptualization and Writing—review & editing; NRD: Conceptualization, Funding acquisition, Project administration, Resources, Investigation, Validation, Supervision, and Writing—review & editing.
Corresponding author
Ethics declarations
Conflict of interest
Author TR declares she has no conflict of interest. Author AS declares he has no conflict of interest. Author KKR declares he has no conflict of interest. Author AJ declares he has no conflict of interest. Author ST declares he has no conflict of interest. Author SV declares he has no conflict of interest. Author NRD declares he has no conflict of interest.
Ethical approval
All the procedures followed in the study were conducted in accordance with the ethical standards of Dr. G.V.N Cancer Institute (ECR/436/INST/TN/2013) and MMHRC (ECR/398/INST/TN/2013/RR-16) and with the 1964 Helsinki Declaration and its later amendments.
Informed consent
Informed consent was obtained from all the individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rajagopal, T., Seshachalam, A., Rathnam, K.K. et al. Impact of xenobiotic-metabolizing gene polymorphisms on breast cancer risk in South Indian women. Breast Cancer Res Treat 186, 823–837 (2021). https://doi.org/10.1007/s10549-020-06028-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-020-06028-z