Metalloestrogens and Endocrine Disruption in Breast Cancer
Main Article Content
Abstract
Metalloestrogens, metals and metalloids capable of mimicking or interfering with estrogen signaling, are emerging environmental contributors to breast cancer risk and endocrine therapy resistance. Compounds such as cadmium, arsenic, aluminum, and chromium bind to estrogen receptors or activate non-genomic pathways such as G protein-coupled estrogen receptor and epidermal growth factor receptor signaling, leading to aberrant proliferation, survival, and oxidative stress. These mechanisms promote epithelial–mesenchymal transition, genomic instability, and therapy resistance in estrogen receptor-positive breast cancer. Cadmium and arsenic can sustain estrogenic signaling and activate MAPK/ERK and PI3K/Akt pathways even under tamoxifen treatment, while arsenic-mediated BRCA1 methylation further reduces drug responsiveness. Limited studies suggest metalloestrogens may also attenuate the efficacy of aromatase inhibitors and selective estrogen receptor degraders by maintaining G protein-coupled estrogen receptor and oxidative stress signaling. Epidemiological evidence correlates elevated cadmium, nickel, and aluminum exposure with increased estrogen receptor-positive breast cancer incidence, yet clinical translation remains incomplete. Understanding metalloestrogen-mediated crosstalk between estrogen receptor-dependent and estrogen receptor-independent pathways will be essential for designing effective combination therapies and integrating environmental toxicology into precision breast cancer management.
Article Details
How to Cite
BURT, Ashlyn et al.
Metalloestrogens and Endocrine Disruption in Breast Cancer.
Medical Research Archives, [S.l.], v. 13, n. 11, dec. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7116>. Date accessed: 26 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i11.7116.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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9. Boszkiewicz K, Moreira H, Sawicka E, Szyjka A, Piwowar A. The Effect of Metalloestrogens on the Effectiveness of Aromatase Inhibitors in a Hormone-Dependent Breast Cancer Cell Model. Cancers. 2023;15(2):457. doi:10.3390/cancers15020457
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13. Saint-Martin F, Marques C, Ren X, Lequy E, Mancini FR, Frénoy P. Associations between dietary exposure to profiles of metalloestrogens and estrogen-receptor positive breast cancer risk in the French E3N cohort. Environmental Health. 2025;24(1):22. doi:10.1186/s12940-025-01167-6
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15. Divekar SD, Li HH, Parodi DA, et al. Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020;41(7):1005-1014. doi:10.1093/carcin/bgz176
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17. Yu X, Filardo EJ, Shaikh ZA. The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells. Toxicol Appl Pharmacol. 2010;245(1):83-90. doi:10.1016/j.taap.2010.02.005
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19. Pupo M, Maggiolini M, Musti AM. GPER Mediates Non-Genomic Effects of Estrogen. In: Eyster KM, ed. Estrogen Receptors: Methods and Protocols. Springer; 2016:471-488. doi:10.1007/978-1-4939-3127-9_37
20. Rasha F, Sharma M, Pruitt K. Mechanisms of endocrine therapy resistance in breast cancer. Molecular and Cellular Endocrinology. 2021;532:111322. doi:10.1016/j.mce.2021.111322
21. Burt A. Cadmium and Arsenic Non-Genomic Mechanisms of Proliferation. BioRender. 2025. https://BioRender.com/pcjf33l
22. Gao X, Yu L, Moore AB, Kissling GE, Waalkes MP, Dixon D. Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways. Environmental Health Perspectives. 2014;123(4):331-336. doi:10.1289/ehp.1408234
23. Li G, Zhang J, Xu Z, Li Z. ERα36 as a Potential Therapeutic Target for Tamoxifen-Resistant Breast Cancer Cell Line Through EGFR/ERK Signaling Pathway. CMAR. 2020;12:265-275. doi:10.2147/CMAR.S226410
24. Yin L, Zhang XT, Bian XW, Guo YM, Wang ZY. Disruption of the ER-α36-EGFR/HER2 Positive Regulatory Loops Restores Tamoxifen Sensitivity in Tamoxifen Resistance Breast Cancer Cells. PLOS ONE. 2014;9(9):e107369. doi:10.1371/journal.pone.0107369
25. Egiebor E, Tulu A, Abou-Zeid N, Oseji OF, Ishaque AB. Oxidative Stress Pathway Mechanisms Induced by Four Individual Heavy Metals (As, Hg, Cd and Pb) and Their Quaternary on MCF-7 Breast Cancer Cells. Journal of Advances in Medicine and Medical Research. 2016;17(7):1-11. doi:10.9734/BJMMR/2016/27687
26. Wang Y, Fang J, Leonard SS, Krishna Rao KM. Cadmium inhibits the electron transfer chain and induces Reactive Oxygen Species. Free Radical Biology and Medicine. 2004;36(11):1434-1443. doi:10.1016/j.freeradbiomed.2004.03.010
27. Burt A. Cadmium, Aluminum, and Arsenic Oxidative Stress Pathway. BioRender. 2025. https://BioRender.com/98v1qhi
28. Mebratu Y, Tesfaigzi Y. How ERK1/2 Activation Controls Cell Proliferation and Cell Death Is Subcellular Localization the Answer? Cell Cycle. 2009;8(8):1168-1175. doi:10.4161/cc.8.8.8147
29. Ariazi E, Cunliffe H, Lewis-Wambi J, et al. Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proceedings of the National Academy of Sciences of the United States of America. 2011. doi:10.1073/pnas.1115188108
30. Sawicka E, Kulbacka J, Drąg-Zalesińska M, Woźniak A, Piwowar A. Effect of Interaction between Chromium(VI) with 17β-Estradiol and Its Metabolites on Breast Cancer Cell Lines MCF-7/WT and MDA-MB-175-VII: Preliminary Study. Molecules. 2023;28(6):2752. doi:10.3390/molecules28062752
31. Shan Z, Wei Z, Shaikh ZA. Suppression of ferroportin expression by cadmium stimulates proliferation, EMT, and migration in triple-negative breast cancer cells. Toxicology and Applied Pharmacology. 2018;356:36 -43. doi:10.1016/j.taap.2018.07.017
32. Wei Z, Shan Z, Shaikh ZA. Epithelial-mesenchymal transition in breast epithelial cells treated with cadmium and the role of Snail. Toxicology and Applied Pharmacology. 2018;344:46-55. doi:10.1016/j.taap.2018.02.022
33. Wei Z, Shaikh ZA. Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling. Toxicology and Applied Pharmacology. 2017;328: 70-80. doi:10.1016/j.taap.2017.05.017
34. Darwish WS, Chen Z, Li Y, Wu Y, Chiba H, Hui SP. Identification of cadmium-produced lipid hydroperoxides, transcriptomic changes in antioxidant enzymes, xenobiotic transporters, and pro-inflammatory markers in human breast cancer cells (MCF7) and protection with fat-soluble vitamins. Environ Sci Pollut Res. 2020;27(2):1978-1990. doi:10.1007/s11356-019-06834-z
35. Burt A. Tamoxifen Resistance Mediated by ERα. BioRender. 2025. https://BioRender.com/l3cer05
36. Bartkowiak-Wieczorek J, Jaros A, Gajdzińska A, et al. The Dual Faces of Oestrogen: The Impact of Exogenous Oestrogen on the Physiological and Pathophysiological Functions of Tissues and Organs. International Journal of Molecular Sciences. 2024;25(15):8167. doi:10.3390/ijms25158167
37. Bhutani K, Vishwakarma S, Yadav P, Yadav MK. The current landscape of aromatase inhibitors for the treatment of estrogen receptor-positive breast carcinoma. J Steroid Biochem Mol Biol. 2025;250:106729. doi:10.1016/j.jsbmb.2025.106729
38. Lewoniewska S, Oscilowska I, Forlino A, Palka J. Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells. Biology. 2021;10(12):1314. doi:10.3390/biology10121314
39. Burt A. Aromatase Inhibitor Mechanism of Action and Resistance. BioRender. 2025. https://BioRender.com/16djls2
40. Amaral C, Borges M, Melo S, Silva ET da, Correia-da-Silva G, Teixeira N. Apoptosis and Autophagy in Breast Cancer Cells following Exemestane Treatment. PLOS ONE. 2012;7(8):e42398. doi:10.1371/journal.pone.0042398
41. Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol. 2022;14:17588359221113694. doi:10.1177/17588359221113694
42. Burt A. SERD Resistance Pathway. BioRender. 2025. https://BioRender.com/sfcs2cf
43. Wang B, Ma M, Dai Y, et al. A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer. European Journal of Medicinal Chemistry. 2024;264:115934. doi:10.1016/j.ejmech.2023.115934
44. Mohapatra P, Preet R, Das D, et al. The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K–AKT–NFκB cascade. Toxicology and Applied Pharmacology. 2014;274(1):168-179. doi:10.1016/j.taap.2013.09.028
45. Zhang HW, Hu JJ, Fu RQ, et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci Rep. 2018;8(1). doi:10.1038/s41598-018-29308-7
2. Wallace DR. Nanotoxicology and Metalloestrogens: Possible Involvement in Breast Cancer. Toxics. 2015;3(4):390-413. doi:10.3390/toxics3040390
3. Darbre PD. Environmental oestrogens, cosmetics and breast cancer. Best Practice & Research Clinical Endocrinology & Metabolism. 2006;20(1):121-143. doi:10.1016/j.beem.2005.09.007
4. Jurkowska K, Kratz EM, Sawicka E, Piwowar A. The impact of metalloestrogens on the physiology of male reproductive health as a current problem of the XXI century. Journal of Physiology and Pharmacology. 2019; 70(3): 337-355. doi: 10.26402/jpp.2019.3.02
5. Hofer N, Diel P, Wittsiepe J, Wilhelm M and Degen GH. Dose- and Route-Dependent Hormonal Activity of the Metalloestrogen Cadmium in the Rat Uterus. Toxicology Letters. 2009;191:123-131. Doi: 10.1016/j.toxlet.2009.08.014
6. Ali I, Damdimopoulou P, Stenius U, Halldin K. Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines. Chem-Biol Interact. 2015;231:44-52. doi:10.1016/j.cbi.2015.02.014
7. Liu J, Yu L, Castro L, et al. A nongenomic mechanism for “metalloestrogenic” effects of cadmium in human uterine leiomyoma cells through G protein-coupled estrogen receptor. Arch Toxicol. 2019;93(10):2773-2785. doi:10.1007/s00204-019-02544-0
8. Qie Y, Qin W, Zhao K, Liu C, Zhao L, Guo LH. Environmental Estrogens and Their Biological Effects through GPER Mediated Signal Pathways. Environmental Pollution. 2021;278:116826. doi:10.1016/j.envpol.2021.116826
9. Boszkiewicz K, Moreira H, Sawicka E, Szyjka A, Piwowar A. The Effect of Metalloestrogens on the Effectiveness of Aromatase Inhibitors in a Hormone-Dependent Breast Cancer Cell Model. Cancers. 2023;15(2):457. doi:10.3390/cancers15020457
10. Stoica A, Katzenellenbogen BS, Martin MB. Activation of estrogen receptor-α by the heavy metal cadmium. Mol Endocrinol. 2000;14(4):545-553. doi:10.1210/me.14.4.545
11. Selmin O, Donovan M, Skovan B, Paine-Murieta G, Romagnolo D. Arsenic induced BRCA1 CpG promoter methylation is associated with the downregulation of ERα and resistance to tamoxifen in MCF7 breast cancer cells and mouse mammary tumor xenografts. International Journal of Oncology. 2019;54(3):869-878. doi:10.3892/ijo.2019.4687
12. Tarhonska K, Janasik B, Roszak J, et al. Environmental exposure to cadmium in breast cancer – association with the Warburg effect and sensitivity to tamoxifen. Biomedicine & Pharmacotherapy. 2023;161:114435. doi:10.1016/j.biopha.2023.114435
13. Saint-Martin F, Marques C, Ren X, Lequy E, Mancini FR, Frénoy P. Associations between dietary exposure to profiles of metalloestrogens and estrogen-receptor positive breast cancer risk in the French E3N cohort. Environmental Health. 2025;24(1):22. doi:10.1186/s12940-025-01167-6
14. Nail AN, Chavez AV, Bailey AN, et al. DNA damage response inhibition is an early event in cadmium-induced breast carcinogenesis. Toxicology and Applied Pharmacology. 2025;502:117439. doi:10.1016/j.taap.2025.117439
15. Divekar SD, Li HH, Parodi DA, et al. Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020;41(7):1005-1014. doi:10.1093/carcin/bgz176
16. Hirao-Suzuki M, Takeda S, Kodama Y, Takiguchi M, Toda A, Ohara M. Metalloestrogenic effects of cadmium are absent in long-term estrogen-deprived MCF-7 cells: Evidence for the involvement of constitutively activated estrogen receptor α and very low expression of G protein-coupled estrogen receptor 1. Toxicology Letters. 2020;319:22-30. doi:10.1016/j.toxlet.2019.10.018
17. Yu X, Filardo EJ, Shaikh ZA. The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells. Toxicol Appl Pharmacol. 2010;245(1):83-90. doi:10.1016/j.taap.2010.02.005
18. Liu Z, Yu X, Shaikh ZA. Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium. Toxicol Appl Pharmacol. 2008;228(3):286-294. doi:10.1016/j.taap.2007.12.017
19. Pupo M, Maggiolini M, Musti AM. GPER Mediates Non-Genomic Effects of Estrogen. In: Eyster KM, ed. Estrogen Receptors: Methods and Protocols. Springer; 2016:471-488. doi:10.1007/978-1-4939-3127-9_37
20. Rasha F, Sharma M, Pruitt K. Mechanisms of endocrine therapy resistance in breast cancer. Molecular and Cellular Endocrinology. 2021;532:111322. doi:10.1016/j.mce.2021.111322
21. Burt A. Cadmium and Arsenic Non-Genomic Mechanisms of Proliferation. BioRender. 2025. https://BioRender.com/pcjf33l
22. Gao X, Yu L, Moore AB, Kissling GE, Waalkes MP, Dixon D. Cadmium and Proliferation in Human Uterine Leiomyoma Cells: Evidence of a Role for EGFR/MAPK Pathways but Not Classical Estrogen Receptor Pathways. Environmental Health Perspectives. 2014;123(4):331-336. doi:10.1289/ehp.1408234
23. Li G, Zhang J, Xu Z, Li Z. ERα36 as a Potential Therapeutic Target for Tamoxifen-Resistant Breast Cancer Cell Line Through EGFR/ERK Signaling Pathway. CMAR. 2020;12:265-275. doi:10.2147/CMAR.S226410
24. Yin L, Zhang XT, Bian XW, Guo YM, Wang ZY. Disruption of the ER-α36-EGFR/HER2 Positive Regulatory Loops Restores Tamoxifen Sensitivity in Tamoxifen Resistance Breast Cancer Cells. PLOS ONE. 2014;9(9):e107369. doi:10.1371/journal.pone.0107369
25. Egiebor E, Tulu A, Abou-Zeid N, Oseji OF, Ishaque AB. Oxidative Stress Pathway Mechanisms Induced by Four Individual Heavy Metals (As, Hg, Cd and Pb) and Their Quaternary on MCF-7 Breast Cancer Cells. Journal of Advances in Medicine and Medical Research. 2016;17(7):1-11. doi:10.9734/BJMMR/2016/27687
26. Wang Y, Fang J, Leonard SS, Krishna Rao KM. Cadmium inhibits the electron transfer chain and induces Reactive Oxygen Species. Free Radical Biology and Medicine. 2004;36(11):1434-1443. doi:10.1016/j.freeradbiomed.2004.03.010
27. Burt A. Cadmium, Aluminum, and Arsenic Oxidative Stress Pathway. BioRender. 2025. https://BioRender.com/98v1qhi
28. Mebratu Y, Tesfaigzi Y. How ERK1/2 Activation Controls Cell Proliferation and Cell Death Is Subcellular Localization the Answer? Cell Cycle. 2009;8(8):1168-1175. doi:10.4161/cc.8.8.8147
29. Ariazi E, Cunliffe H, Lewis-Wambi J, et al. Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proceedings of the National Academy of Sciences of the United States of America. 2011. doi:10.1073/pnas.1115188108
30. Sawicka E, Kulbacka J, Drąg-Zalesińska M, Woźniak A, Piwowar A. Effect of Interaction between Chromium(VI) with 17β-Estradiol and Its Metabolites on Breast Cancer Cell Lines MCF-7/WT and MDA-MB-175-VII: Preliminary Study. Molecules. 2023;28(6):2752. doi:10.3390/molecules28062752
31. Shan Z, Wei Z, Shaikh ZA. Suppression of ferroportin expression by cadmium stimulates proliferation, EMT, and migration in triple-negative breast cancer cells. Toxicology and Applied Pharmacology. 2018;356:36 -43. doi:10.1016/j.taap.2018.07.017
32. Wei Z, Shan Z, Shaikh ZA. Epithelial-mesenchymal transition in breast epithelial cells treated with cadmium and the role of Snail. Toxicology and Applied Pharmacology. 2018;344:46-55. doi:10.1016/j.taap.2018.02.022
33. Wei Z, Shaikh ZA. Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling. Toxicology and Applied Pharmacology. 2017;328: 70-80. doi:10.1016/j.taap.2017.05.017
34. Darwish WS, Chen Z, Li Y, Wu Y, Chiba H, Hui SP. Identification of cadmium-produced lipid hydroperoxides, transcriptomic changes in antioxidant enzymes, xenobiotic transporters, and pro-inflammatory markers in human breast cancer cells (MCF7) and protection with fat-soluble vitamins. Environ Sci Pollut Res. 2020;27(2):1978-1990. doi:10.1007/s11356-019-06834-z
35. Burt A. Tamoxifen Resistance Mediated by ERα. BioRender. 2025. https://BioRender.com/l3cer05
36. Bartkowiak-Wieczorek J, Jaros A, Gajdzińska A, et al. The Dual Faces of Oestrogen: The Impact of Exogenous Oestrogen on the Physiological and Pathophysiological Functions of Tissues and Organs. International Journal of Molecular Sciences. 2024;25(15):8167. doi:10.3390/ijms25158167
37. Bhutani K, Vishwakarma S, Yadav P, Yadav MK. The current landscape of aromatase inhibitors for the treatment of estrogen receptor-positive breast carcinoma. J Steroid Biochem Mol Biol. 2025;250:106729. doi:10.1016/j.jsbmb.2025.106729
38. Lewoniewska S, Oscilowska I, Forlino A, Palka J. Understanding the Role of Estrogen Receptor Status in PRODH/POX-Dependent Apoptosis/Survival in Breast Cancer Cells. Biology. 2021;10(12):1314. doi:10.3390/biology10121314
39. Burt A. Aromatase Inhibitor Mechanism of Action and Resistance. BioRender. 2025. https://BioRender.com/16djls2
40. Amaral C, Borges M, Melo S, Silva ET da, Correia-da-Silva G, Teixeira N. Apoptosis and Autophagy in Breast Cancer Cells following Exemestane Treatment. PLOS ONE. 2012;7(8):e42398. doi:10.1371/journal.pone.0042398
41. Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol. 2022;14:17588359221113694. doi:10.1177/17588359221113694
42. Burt A. SERD Resistance Pathway. BioRender. 2025. https://BioRender.com/sfcs2cf
43. Wang B, Ma M, Dai Y, et al. A novel scaffold long-acting selective estrogen receptor antagonist and degrader with superior preclinical profile against ER+ breast cancer. European Journal of Medicinal Chemistry. 2024;264:115934. doi:10.1016/j.ejmech.2023.115934
44. Mohapatra P, Preet R, Das D, et al. The contribution of heavy metals in cigarette smoke condensate to malignant transformation of breast epithelial cells and in vivo initiation of neoplasia through induction of a PI3K–AKT–NFκB cascade. Toxicology and Applied Pharmacology. 2014;274(1):168-179. doi:10.1016/j.taap.2013.09.028
45. Zhang HW, Hu JJ, Fu RQ, et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci Rep. 2018;8(1). doi:10.1038/s41598-018-29308-7