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Licensed Unlicensed Requires Authentication Published by De Gruyter December 25, 2020

The possible role of arsenic and gene-arsenic interactions in susceptibility to breast cancer: a systematic review

Roxana Moslehi ORCID logo, Cristy Stagnar, Sneha Srinivasan, Pawel Radziszowski and David O. Carpenter


The roles of many environmental contaminants in increasing breast cancer risk remain controversial. Arsenic (As) is a major global environmental contaminant and carcinogen. We conducted a systematic review of the role of As and gene-arsenic interactions in susceptibility to breast cancer. Following a systematic literature search using well-defined inclusion/exclusion criteria, a total of 15 epidemiologic studies (two meta-analyses, three systematic reviews, three cohort studies, two case-control studies, and five cross-sectional studies) were reviewed. In addition, several animal, in vitro, in vivo, and in silico (i.e., computer modeling) studies provided mechanistic insights into the association between As and breast cancer. Our review suggests a possible overall main effect of As on breast cancer risk. The evidence for an effect of gene-As interactions on breast cancer risk is strong. Studies that measured levels of As metabolites among participants and/or evaluated interactions between As exposure and genetic or epigenetic factors generally reported positive associations with breast cancer risk. Our analysis of the Comparative Toxicogenomics and the Ingenuity Pathway Analysis Databases provided further evidence for As-gene interactions and their effects on breast cancer-related biologic pathways. Our findings provide potential leads for future epidemiologic studies of As-associated cancer risks and interventions to reduce population exposure.

Corresponding author: Roxana Moslehi, Ph.D., Associate Professor, School of Public Health, Albany, USA; and Cancer Research Center, University at Albany, State University of New York (SUNY), Albany, NY, 12144, USA, E-mail:

  1. Research funding: There was no funding involved for this work.

  2. Author contributions: RM conceived the study, mentored students on literature search and review, independently reviewed all identified papers, and drafted the manuscript. CS and PR conducted literature search and review. SR helped with literature review and tabulation. DOC helped with the strategy for literature review and interpretation of findings.

  3. Competing interests: Authors declare no conflict of interest.

  4. Informed consent: Informed consent is not applicable.

  5. Ethical approval: The conducted research is not related to either human or animal use.


1. Ferlay, J, Colombet, M, Soerjomataram, I, Mathers, C, Parkin, DM, Pineros, M, et al.. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Canc 2019;144:1941–53. in Google Scholar

2. American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer Society; 2020.Search in Google Scholar

3. Moslehi, R, Freedman, E, Zeinomar, N, Veneroso, C, Levine, PH. Importance of hereditary and selected environmental risk factors in the etiology of inflammatory breast cancer: a case-comparison study. BMC Canc 2016;16:334. in Google Scholar

4. Hiatt, RA, Brody, JG. Environmental determinants of breast cancer. Annu Rev Publ Health 2018;39:113–33. in Google Scholar

5. Peto, R. Cancer, genes, and the environment. N Engl J Med 2000;343:1495. discussion 1495-6.10.1056/NEJM200011163432013Search in Google Scholar

6. Ronchetti, SA, Novack, GV, Bianchi, MS, Crocco, MC, Duvilanski, BH, Cabilla, JP. In vivo xenoestrogenic actions of cadmium and arsenic in anterior pituitary and uterus. Reproduction 2016;152:1–10. in Google Scholar

7. Gundert-Remy, U, Damm, G, Foth, H, Freyberger, A, Gebel, T, Golka, K, et al.. High exposure to inorganic arsenic by food: the need for risk reduction. Arch Toxicol 2015;89:2219–27. in Google Scholar

8. Palma-Lara, I, Martinez-Castillo, M, Quintana-Perez, JC, Arellano-Mendoza, MG, Tamay-Cach, F, Valenzuela-Limon, OL, et al.. Arsenic exposure: a public health problem leading to several cancers. Regul Toxicol Pharmacol 2020;110:104539. in Google Scholar

9. Rehman, K, Fatima, F, Waheed, I, Akash, MSH. Prevalence of exposure of heavy metals and their impact on health consequences. J Cell Biochem 2018;119:157–84. in Google Scholar

10. Straif, K, Benbrahim-Tallaa, L, Baan, R, Grosse, Y, Secretan, B, El Ghissassi, F, et al.. A review of human carcinogens--Part C: metals, arsenic, dusts, and fibres. Lancet Oncol 2009;10:453–4. in Google Scholar

11. Bardach, AE, Ciapponi, A, Soto, N, Chaparro, MR, Calderon, M, Briatore, A, et al.. Epidemiology of chronic disease related to arsenic in Argentina: a systematic review. Sci Total Environ 2015;538:802–16. in Google Scholar

12. Chen, QY, DesMarais, T, Costa, M. Metals and mechanisms of carcinogenesis. Annu Rev Pharmacol Toxicol 2019;59:537–54. in Google Scholar

13. Jouybari, L, Saei Ghare Naz, M, Sanagoo, A, Kiani, F, Sayehmiri, F, Sayehmiri, K, et al.. Toxic elements as biomarkers for breast cancer: a meta-analysis study. Canc Manag Res 2018;10:69–79. in Google Scholar

14. Gamboa-Loira, B, Cebrian, ME, Franco-Marina, F, Lopez-Carrillo, L. Arsenic metabolism and cancer risk: a meta-analysis. Environ Res 2017;156:551–8. in Google Scholar

15. Khanjani, N, Jafarnejad, AB, Tavakkoli, L. Arsenic and breast cancer: a systematic review of epidemiologic studies. Rev Environ Health 2017;32:267–77. in Google Scholar

16. Romagnolo, DF, Daniels, KD, Grunwald, JT, Ramos, SA, Propper, CR, Selmin, OI. Epigenetics of breast cancer: modifying role of environmental and bioactive food compounds. Mol Nutr Food Res 2016;60:1310–29. in Google Scholar

17. White, AJ, O’Brien, KM, Niehoff, NM, Carroll, R, Sandler, DP. Metallic air pollutants and breast cancer risk in a nationwide cohort study. Epidemiology 2019;30:20–8. in Google Scholar

18. Zhang, R, Zhang, X, Wu, K, Wu, H, Sun, Q, Hu, FB, et al.. Rice consumption and cancer incidence in US men and women. Int J Canc 2016;138:555–64. in Google Scholar

19. Liu, R, Nelson, DO, Hurley, S, Hertz, A, Reynolds, P. Residential exposure to estrogen disrupting hazardous air pollutants and breast cancer risk: the California Teachers Study. Epidemiology 2015;26:365–73. in Google Scholar

20. O’Brien, KM, White, AJ, Jackson, BP, Karagas, MR, Sandler, DP, Weinberg, CR. Toenail-based metal concentrations and young-onset breast cancer. Am J Epidemiol 2019;188:646–55. in Google Scholar

21. Gamboa-Loira, B, Cebrian, ME, Salinas-Rodriguez, A, Lopez-Carrillo, L. Genetic susceptibility to breast cancer risk associated with inorganic arsenic exposure. Environ Toxicol Pharmacol 2017;56:106–13. in Google Scholar

22. Michel-Ramirez, G, Recio-Vega, R, Lantz, RC, Gandolfi, AJ, Olivas-Calderon, E, Chau, BT, et al.. Assessment of YAP gene polymorphisms and arsenic interaction in Mexican women with breast cancer. J Appl Toxicol 2020;40:342–51. in Google Scholar

23. Ajayi, O, Charles-Davies, M, Anetor, J, Ademola, A. Pituitary, gonadal, thyroid hormones and endocrine disruptors in pre and postmenopausal Nigerian women with ER-, PR- and HER-2-positive and negative breast cancers. Med Sci 2018;6. in Google Scholar

24. Michel-Ramirez, G, Recio-Vega, R, Ocampo-Gomez, G, Palacios-Sanchez, E, Delgado-Macias, M, Delgado-Gaona, M, et al.. Association between YAP expression in neoplastic and non-neoplastic breast tissue with arsenic urinary levels. J Appl Toxicol 2017;37:1195–202. in Google Scholar

25. Joo, NS, Kim, SM, Jung, YS, Kim, KM. Hair iron and other minerals’ level in breast cancer patients. Biol Trace Elem Res 2009;129:28–35. in Google Scholar

26. Schlawicke Engstrom, K, Nermell, B, Concha, G, Stromberg, U, Vahter, M, Broberg, K. Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res 2009;667:4–14. in Google Scholar

27. Parodi, DA, Greenfield, M, Evans, C, Chichura, A, Alpaugh, A, Williams, J, et al.. Alteration of mammary gland development and gene expression by in utero exposure to arsenic. Reprod Toxicol 2015;54:66–75. in Google Scholar

28. Egiebor, E, Tulu, A, Abou-Zeid, N, Aighewi, IT, Ishaque, A. The kinetic signature of toxicity of four heavy metals and their mixtures on MCF7 breast cancer cell line. Int J Environ Res Publ Health 2013;10:5209–20. in Google Scholar

29. Smeester, L, Rager, JE, Bailey, KA, Guan, X, Smith, N, Garcia-Vargas, G, et al.. Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol 2011;24:165–7. in Google Scholar

30. Wendt, C, Margolin, S. Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol 2019;58:135–46. in Google Scholar

31. Couch, FJ, Nathanson, KL, Offit, K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 2014;343:1466–70. in Google Scholar

32. Foulkes, WD. Inherited susceptibility to common cancers. N Engl J Med 2008;359:2143–53. in Google Scholar

33. Navarro Silvera, SA, Rohan, TE. Trace elements and cancer risk: a review of the epidemiologic evidence. Cancer Causes Control 2007;18:7–27. in Google Scholar

34. Lopez-Carrillo, L, Hernandez-Ramirez, RU, Gandolfi, AJ, Ornelas-Aguirre, JM, Torres-Sanchez, L, Cebrian, ME. Arsenic methylation capacity is associated with breast cancer in northern Mexico. Toxicol Appl Pharmacol 2014;280:53–9. in Google Scholar

35. Moslehi, R, Chatterjee, N, Church, TR, Chen, J, Yeager, M, Weissfeld, J, et al.. Cigarette smoking, N-acetyltransferase genes and the risk of advanced colorectal adenoma. Pharmacogenomics 2006;7:819–29. in Google Scholar

36. Tan, XL, Moslehi, R, Han, W, Spivack, SD. Haplotype-tagging single nucleotide polymorphisms in the GSTP1 gene promoter and susceptibility to lung cancer. Canc Detect Prev 2009;32:403–15. in Google Scholar

37. Wang, Z, Yang, C. Metal carcinogen exposure induces cancer stem cell-like property through epigenetic reprograming: a novel mechanism of metal carcinogenesis. Semin Canc Biol 2019;57:95–104. in Google Scholar

38. Kramer, A, Green, J, Pollard, JJr., Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 2014;30:523–30. in Google Scholar

39. Davis, AP, Murphy, CG, Rosenstein, MC, Wiegers, TC, Mattingly, CJ. The Comparative Toxicogenomics Database facilitates identification and understanding of chemical-gene-disease associations: arsenic as a case study. BMC Med Genom 2008;1:48. in Google Scholar

40. Goodson, WH3rd, Lowe, L, Carpenter, DO, Gilbertson, M, Manaf Ali, A, Lopez de Cerain Salsamendi, A, et al.. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015;36:S254-96. in Google Scholar

Received: 2020-06-23
Accepted: 2020-12-06
Published Online: 2020-12-25
Published in Print: 2021-12-20

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