Environmental Science and Pollution Research

, Volume 26, Issue 9, pp 8459–8467 | Cite as

A mini review of bisphenol A (BPA) effects on cancer-related cellular signaling pathways

  • Samira Nomiri
  • Reyhane HoshyarEmail author
  • Concetta Ambrosino
  • Charles R. Tyler
  • Borhan MansouriEmail author
Review Article


Bisphenol A (BPA) is a plasticizer used widely in many industrial products and is now well established as an endocrine-disrupting chemical (EDC). BPA readily leaches out from these products into the environment and into foodstuffs (from packaging materials) and human exposure can be considerable. Many studies have shown that BPA exposure is associated with a range of chronic human health conditions, including diabetes, cardiovascular disorders, polycystic ovarian disease, hepatotoxicity, and various types of cancer. BPA exerts its effects through deregulating cell signaling pathways associated with cell growth, proliferation, migration, invasion, and apoptosis. Previous studies on the molecular mechanisms of BPA have illustrated a variety of pathways impaired at very low exposure concentrations and that stimulate cellular responses relating to tumorigenesis both in cancer onset and progression. In this mini review, the recent advancements made through in vitro analyses are reported on for the effect of BPA on various cellular signaling pathways focusing on the signaling pathways that play a major role in carcinogenesis.


Bisphenol A Cancer Signal pathway Toxicity 



bisphenol A


hormone-disrupting compounds


environmental protection agency


body weight



The authors gratefully acknowledge the support from the Research Council of Birjand University of Medical Sciences. The contribution of the Cellular and Molecular Research Center and Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, is also sincerely appreciated.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg Å (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Ame J Hum Gen 72:1117–1130CrossRefGoogle Scholar
  2. Betancourt AM, Eltoum IA, Desmond RA, Russo J, Lamartiniere CA (2010) In utero exposure to bisphenol A shifts the window of susceptibility for mammary carcinogenesis in the rat. Environ Health Perspect 118:1614–1619CrossRefGoogle Scholar
  3. Bilancio A, Bontempo P, DI donato M, Conte M, Giovannelli P, Altucci L, Migliaccio A, Castoria G (2017) Bisphenol A induces cell cycle arrest in primary and prostate cancer cells through EGFR/ERK/p53 signaling pathway activation. Oncotarget 8:115620CrossRefGoogle Scholar
  4. Bontempo P, Mita L, Doto A, Miceli M, Nebbioso A, Lepore I, Franci G, Menafra R, Carafa V, Conte M (2009) Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells. J Transl Med 7:48–56CrossRefGoogle Scholar
  5. Bouskine A, Nebout M, Brücker-Davis F, Banahmed M, Fenichel P (2009) Low doses of Bisphenol A promote human seminoma cell proliferation by activating PKA and PKG via a membrane G-protein-coupled estrogen receptor. Environ Health Perspect 117:1053–1058Google Scholar
  6. Carchia E, Porreca I, Almeida P, D’Angelo F, Cuomo D, Ceccarelli M, DE Felice M, Mallardo M, Ambrosino C (2015) Evaluation of low doses BPA-induced perturbation of glycemia by toxicogenomics points to a primary role of pancreatic islets and to the mechanism of toxicity. Cell Death Dis 6:1959–1968CrossRefGoogle Scholar
  7. Castillo sanchez R, Gomez R, Perez salazar E (2016) Bisphenol A induces migration through a GPER-, FAK-, Src-, and ERK2-dependent pathway in MDA-MB-231 breast cancer cells. Chem Res Toxicol 29:285–295CrossRefGoogle Scholar
  8. Chen ZJ, Yang XL, Liu H, Wei W, Zhang KS, Huang HB, Giesy JP, Liu HL, Du J, Wang HS (2015) Bisphenol A modulates colorectal cancer protein profile and promotes the metastasis via induction of epithelial to mesenchymal transitions. Arch Toxicol 89:1371–1381CrossRefGoogle Scholar
  9. Chibazakura T, Kamachi K, Ohara M, Tane S, Yoshikawa H, Roberts JM (2011) Cyclin A promotes Sphase entry via interaction with the replication licensing factor Mcm7. Mol Cell Biol 31: 248–255Google Scholar
  10. Dairkee SH, Luciani-Torres MG, Moore DH, Goodson WH (2013) Bisphenol A induced inactivation of the p53 axis underlying deregulation of proliferation kinetics, and cell death in non-malignant human breast epithelial cells. Carcinogenesis 34:703–712CrossRefGoogle Scholar
  11. Dekant W, Völkel W (2008) Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures. Toxicol Appl Pharmacol 228:114–134CrossRefGoogle Scholar
  12. Delgado M, Ribeiro-varandas E (2015) Bisphenol A at the reference level counteracts doxorubicin transcriptional effects on cancer related genes in HT29 cells. Toxicol in Vitro 29:2009–2014CrossRefGoogle Scholar
  13. Fernandez SV, Huang Y, Snider KE, Zhou Y, Pogash TJ, Russo J (2012) Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol 41:369–377Google Scholar
  14. Ferreira LL, Couto R, Oliveira PJ (2015) Bisphenol A as epigenetic modulator: setting the stage for carcinogenesis? Europ J Clin Inv 45:32–36CrossRefGoogle Scholar
  15. Hanet N, Lancon A, Delmas D, Jannin B, Chagnon MC, Cherkaoui-malki M, Latruffe N, Artur Y, Heydel JM (2008) Effects of endocrine disruptors on genes associated with 17β-estradiol metabolism and excretion. Steroids 73:1242–1251CrossRefGoogle Scholar
  16. Hassan ZK, Elobeid MA, Virk P, Omer SA, Elamin M, Daghestani MH, Alolayan EM (2012) Bisphenol A induces hepatotoxicity through oxidative stress in rat model. Oxidative Med Cell Longev 2012:1–6CrossRefGoogle Scholar
  17. Hoffmann M, Rak A, Ptak A (2018) Bisphenol A and its derivatives decrease expression of chemerin, which reverses its stimulatory action in ovarian cancer cells. Toxicol Lett 291:61–69CrossRefGoogle Scholar
  18. Hofmann MC, Narisawa S, Hess RA, Millán JL (1992) Immortalization of germ cells and somatic testicular cells using the SV40 large T antigen. Exp Cell Res 201:417–435CrossRefGoogle Scholar
  19. Hui L, Li H, Lu G, Chen Z, Sun W, Shi Y, Fu Z, Huang B, Zhu X, Lu W, Xia D, Wu Y (2018) Low dose of bisphenol A modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci 164:527–538.
  20. Hwang KA, Park MA, Kang NH, Yi BR, Hyun SH, Jeung EB, Choi KC (2013) Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways. Toxicol Appl Pharmacol 272:637–646CrossRefGoogle Scholar
  21. Jalal N, Surendranath AR, Pathak JL, Yu S, Chung CY (2018) Bisphenol A (BPA) the mighty and the mutagenic. Toxicol Rep 5:76–84Google Scholar
  22. Jenkins S, Raghuraman N, Eltoum I, Carpenter M, Russo J, Lamartiniere CA (2009) Oral exposure to bisphenol A increases dimethylbenzanthracene-induced mammary cancer in rats. Environ Health Perspect 117:910–915CrossRefGoogle Scholar
  23. Jones P, George A (2004) The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci CMLS 61:682–699CrossRefGoogle Scholar
  24. Kang NH, Ka H, Hr L, Dw C, Kc C (2013) Resveratrol regulates the cell viability promoted by 17β-estradiol or bisphenol A via down-regulation of the cross-talk between estrogen receptor α and insulin growth factor-1 receptor in BG-1 ovarian cancer cells. Food Chem Toxicol 59:373–379CrossRefGoogle Scholar
  25. Kim SH, Kim CW, Jeon SY, Go RE, Hwang KA, Choi KC (2014) Chemopreventive and chemotherapeutic effects of genistein, a soy isoflavone, upon cancer development and progression in preclinical animal models. Lab Animal Res 30:143–150CrossRefGoogle Scholar
  26. Kim YS, Choi KC, Hwang KA (2015a) Genistein suppressed epithelial–mesenchymal transition and migration efficacies of BG-1 ovarian cancer cells activated by estrogenic chemicals via estrogen receptor pathway and downregulation of TGF-β signaling pathway. Phytomedicine 22:993–999CrossRefGoogle Scholar
  27. Kim YS, Hwang KA, Hyun SH, Nam KH, Lee CK, Choi KC (2015b) Bisphenol A and nonylphenol have the potential to stimulate the migration of ovarian cancer cells by inducing epithelial–mesenchymal transition via an estrogen receptor dependent pathway. Chem Res Toxicol 28:662–671CrossRefGoogle Scholar
  28. Kuroda N, Kinoshita Y, Sun Y, Wada M, Kishikawa N, Nakashima K, Makino T, Nakazawa H (2003) Measurement of bisphenol A levels in human blood serum and ascitic fluid by HPLC using a fluorescent labeling reagent. J Pharm Biomed Anal 30:1743–1749CrossRefGoogle Scholar
  29. Ma XF, Zhang J, Shuai HL, Guan BZ, Luo X, Yan RL (2015) IKKβ/NF-κB mediated the low doses of bisphenol A induced migration of cervical cancer cells. Arch Biochem Biophys 573:52–58CrossRefGoogle Scholar
  30. Mileva G, Baker S, Konkle A, Bielajew C (2014) Bisphenol-A: epigenetic reprogramming and effects on reproduction and behavior. Int J Environ Res Public Health 11:7537–7561CrossRefGoogle Scholar
  31. Mlynarcikova A, Macho L, Fickova M (2013) Bisphenol A alone or in combination with estradiol modulates cell cycle- and apoptosis-related proteins and genes in MCF7 cells. Endocr Regul 47:189–199CrossRefGoogle Scholar
  32. Moscovitz JE, Nahar MS, Shalat SL, Slitt AL, Dolinoy DC, Aleksunes LM (2016) Correlation between conjugated bisphenol A concentrations and efflux transporter expression in human fetal livers. Drug Metab Dispos 44:1061–1065. CrossRefGoogle Scholar
  33. Murata M, Kang JH (2018) Bisphenol A (BPA) and cell signaling pathways. Biotechnol Adv 36:311–327CrossRefGoogle Scholar
  34. Park MA, Choi KC (2014) Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models. Chem Res Toxicol 27:119–128CrossRefGoogle Scholar
  35. Pivnenko K, Pedersen GA, Eriksson E, Astrup TF (2015) Bisphenol A and its structural analogues in household waste paper. Waste Manag 44:39–47CrossRefGoogle Scholar
  36. Porreca I, Severino LU, D’Angelo F, Cuomo D, Ceccarelli M, Altucci L, Amendola E, Nebbioso A, Mallardo M, De Felice M (2016) “Stockpile” of slight transcriptomic changes determines the indirect genotoxicity of low-dose BPA in thyroid cells. PLoS One 11:e0151618CrossRefGoogle Scholar
  37. Prins GS, Hu W-Y, Shi G-B, Hu D-P, Majumdar S, Li G, Huang K, Nelles JL, Ho S-M, Walker CL, Kajdacsy-Balla A, van Breemen RB (2014) Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology 155:805–817Google Scholar
  38. Ptak A, Gregoraszczuk EL (2012) Bisphenol A induces leptin receptor expression, creating more binding sites for leptin, and activates the JAK/Stat, MAPK/ERK and PI3K/Akt signalling pathways in human ovarian cancer cell. Toxicol Lett 210:332–337CrossRefGoogle Scholar
  39. Ptak A, Hoffmann M, Gruca I, Barć J (2014) Bisphenol A induce ovarian cancer cell migration via the MAPK and PI3K/Akt signalling pathways. Toxicol Lett 229:357–365CrossRefGoogle Scholar
  40. Ptak A, Wróbel A, Gregoraszczuk EL (2011) Effect of bisphenol-A on the expression of selected genes involved in cell cycle and apoptosis in the OVCAR-3 cell line. Toxicol Lett 202:30–35CrossRefGoogle Scholar
  41. Pupo M, Pisano A, Lappano R, Santolla MF, De Francesco EM, Abonante S, Rosano C, Maggiolini M (2012) Bisphenol A induces gene expression changes and proliferative effects through GPER in breast cancer cells and cancer-associated fibroblasts. Environ Health Perspect 120:1177–1182CrossRefGoogle Scholar
  42. Qin XY, Fukuda T, Yang L, Zaha H, Akanuma H, Zeng Q, Yoshinaga J, Sone H (2012) Effects of bisphenol A exposure on the proliferation and senescence of normal human mammary epithelial cells. Cancer Biol Ther 13:296–306CrossRefGoogle Scholar
  43. Qiu W, Zhao Y, Yang M, Farajzadeh M, Pan C, Wayne NL (2016) Actions of bisphenol A and bisphenol S on the reproductive neuroendocrine system during early development in zebrafish. Endocrinology 157:636–647CrossRefGoogle Scholar
  44. Shafei A, Matboul M, Mostafa E, Al Sannat S, Abdelrahman M, Lewis B, Muhammad B, Mohamed S, Mostafa RM (2018) Stop eating plastic, molecular signaling of bisphenol A in breast cancer. Environ Sci Pollut Res:1–7Google Scholar
  45. Sheng Z-G, Huang W, Liu Y-X, Zhu B-Z (2013) Bisphenol A at a low concentration boosts mouse spermatogonial cell proliferation by inducing the G protein-coupled receptor 30 expression. Toxicol Appl Pharmacol 267:88–94CrossRefGoogle Scholar
  46. Song H, Zhang T, Yang P, Li M, Yang Y, Wang Y, Du J, Pan K, Zhang K (2015) Low doses of bisphenol A stimulate the proliferation of breast cancer cells via ERK1/2/ERRγ signals. Toxicol in Vitro 30:521–528CrossRefGoogle Scholar
  47. Terasaka H, Kadoma Y, Sakagami H, Fujisawa S (2005) Cytotoxicity and apoptosis-inducing activity of bisphenol A and hydroquinone in HL-60 cells. Anticancer Res 25: 2241–2247Google Scholar
  48. Wang J, Jenkins S, Lamartiniere CA (2014) Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein. BMC Cancer 14:379CrossRefGoogle Scholar
  49. Wang KH, Kao AP, Chang CC, Lin TC, Kuo TC (2013) Bisphenol A at environmentally relevant doses induces cyclooxygenase-2 expression and promotes invasion of human mesenchymal stem cells derived from uterine myoma tissue. Taiwan J Obs Gynecol 52:246–252CrossRefGoogle Scholar
  50. Wang KH, Kao AP, Chang CC, Lin TC, Kuo TC (2015a) Bisphenol A-induced epithelial to mesenchymal transition is mediated by cyclooxygenase-2 up-regulation in human endometrial carcinoma cells. Reprod Toxicol 58:229–233CrossRefGoogle Scholar
  51. Wang ZY, Lu J, Zhang YZ, Zhang M, Liu T, Qu XL (2015b) Effect of Bisphenol A on invasion ability of human trophoblastic cell line BeWo. Int J Clin Exp Pathol 8:14355Google Scholar
  52. Wetherill YB, Petre CE, Monk KR, Puga A, Knudsen KE (2002) The xenoestrogen bisphenol A induces inappropriate androgen receptor activation and mitogenesis in prostatic adenocarcinoma cells 1. This work was supported by NIH training grant ES07250-13 (to YBW; environmental mutagenesis and cancer) and NIH grant R01 CA93404-01 (to KEK). 1. Mol Cancer Ther 1:515–524Google Scholar
  53. Yaguchi T (2018) The endocrine disruptor bisphenol A promotes nuclear ERRγ translocation, facilitating cell proliferation of Grade I endometrial cancer cells via EGF-dependent and EGF-independent pathways. Mol Cell Biochem 27:1–10Google Scholar
  54. Yang L, Luo L, Ji W, Gong C, Wu D, Huang H, Liu Q, Xia B, Hu G, Zhang W (2013) Effect of low dose bisphenol A on the early differentiation of human embryonic stem cells into mammary epithelial cells. Toxicol Lett 218:187–193CrossRefGoogle Scholar
  55. Zhang KS, Chen HQ, Chen YS, Qiu KF, Zheng XB, Li GC, Yang HD, Wen CJ (2014) Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway. Biomed Pharmacother 68:1037–1043CrossRefGoogle Scholar
  56. Zhang W, Fang Y, Shi X, Zhang M, Wang X, Tan Y (2012) Effect of bisphenol A on the EGFR-STAT3 pathway in MCF-7 breast cancer cells. Mol Med Rep 5:41–47CrossRefGoogle Scholar
  57. Zhang XL, Wang HS, Liu N, Ge LC (2015) Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals. Arch Biochem Biophys 585:10–16CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Student Research CommitteeBirjand University of Medical SciencesBirjandIran
  2. 2.Cellular and Molecular Research Center, Clinical Biochemistry DepartmentBirjand University of Medical SciencesBirjandIran
  3. 3.Department of Microbiology and Molecular GeneticsMichigan State UniversityEast LansingUSA
  4. 4.Department of Science and TechnologyUniversity of SannioBeneventoItaly
  5. 5.IRGSBiogemAvellinoItaly
  6. 6.IEOS-CNRNaplesItaly
  7. 7.Biosciences, College of Life and Environmental SciencesUniversity of ExeterExeterUnited Kingdom
  8. 8.Medical Toxicology and Drug Abuse Research Center (MTDRC)Birjand University of Medical SciencesBirjandIran

Personalised recommendations