Skip to main content

Advertisement

SpringerLink
Log in

The modulatory role of low concentrations of bisphenol A on tamoxifen-induced proliferation and apoptosis in breast cancer cells

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Selective estrogen receptor modulators such as tamoxifen (TAM) significantly reduce the risks of developing estrogen receptor–positive (ER+) breast cancer. Low concentrations (nanomolar range) of bisphenol A (BPA) shows estrogenic effects and further promotes the proliferation of hormone-dependent breast cancer cells. However, whether or not BPA can influence TAM-treatment resistance in breast cancer has not drawn much attention. In the current study, low concentrations of BPA reduced TAM-induced cytotoxicity of MCF-7 cells, which was proved by the suppression of cell apoptosis, transition of cell cycle from G1 to S phase, and upregulation of cyclin D1 and ERα. Simultaneously, the mRNA levels of estrogen-related receptor γ (ERRγ) and its coactivators, peroxisome proliferation–activated receptor γ coactivator-1α (PGC-1α), and PGC-1β, were increased. However, the similar effects were not observed in MDA-MB-231 cells. Our results indicated that low concentrations of BPA decreased the sensitivity of TAM in MCF-7 cells rather than in MDA-MB-231 cells. These different actions likely involved the interaction of relative receptors and coactivators. This study provided a possible support that the exposure of BPA in environmental media may potentially induce TAM resistance to breast cancer treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abad MC, Askari H, O’Neill J, Klinger AL, Milligan C, Lewandowski F, Springer B, Spurlino J, Rentzeperis D (2008) Structural determination of estrogen-related receptor γ in the presence of phenol derivative compounds. J Steroid Biochem Mol Biol 108(1–2):44–54

    Article  CAS  Google Scholar 

  • Andersen HR, Andersson AM, Arnold SF, Autrup H, Barfoed M, Beresford NA, Bjerregaard P, Christiansen LB, Gissel B, Hummel R, Jørgensen EB, Korsgaard B, Guevel RL, Leffers H, McLachlan J, Møller A, Nielsen JB, Olea N, Oles-Karasko A, Pakdel F, Pedersen KL, Perez P, Skakkebœk NE, Sonnenschein C, Soto AM, Sumpter JP, Thorpe SM, Grandjean P (1999) Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals. Environ Health Persp 107(Suppl 1):89–108

    Article  CAS  Google Scholar 

  • 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(8):1371–1381

    Article  CAS  Google Scholar 

  • Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Mastro LD, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol 25(5):486–492

    Article  CAS  Google Scholar 

  • Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF, Firestone GL (1999) Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res 59(6):1244–1251

    CAS  Google Scholar 

  • Dairkee SH, Luciani-torres MG, Moore DH (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 34:703–712

    Article  CAS  Google Scholar 

  • 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(8):2009–2014

    Article  CAS  Google Scholar 

  • Diel P, Olff S, Schmidt S, Michna H (2002) Effects of the environmental estrogens bisphenol A, o, p′-DDT, p-tert-octylphenol and coumestrol on apoptosis induction, cell proliferation and the expression of estrogen sensitive molecular parameters in the human breast cancer cell line MCF-7. J Steroid Biochem Mol Biol 80(1):61–70

    Article  CAS  Google Scholar 

  • Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411(6835):342–348

    Article  CAS  Google Scholar 

  • Geens T, Aerts D, Berthot C, Bourguignon JP, Goeyens L, Lecomte P, Maghuin-Rogister G, Pironnet AM, Pussemier L, Scippo ML, Loco JV, Covaci A (2012) A review of dietary and non-dietary exposure to bisphenol-A. Food Chem Toxicol 50(10):3725–3740

    Article  CAS  Google Scholar 

  • Giguère V (2008) Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev 29(6):677–696

    Article  CAS  Google Scholar 

  • Girard BJ, Anderson TMR, Welch SL, Nicely J, Seewaldt VL, Ostrander JH (2015) Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from tam-induced cell death. PLoS One 10(3):e0121206

    Article  CAS  Google Scholar 

  • Goodson WH III, Luciani MG, Sayeed SA, Jaffee IM, Moore IIDH, Dairkee SH (2011) Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women. Carcinogenesis 32(11):1724–1733

    Article  CAS  Google Scholar 

  • Gould JC, Leonard LS, Maness SC, Wagner BL, Conner K, Zacharewski T, Safe S, McDonnell DP, Gaido KW (1998) Bisphenol A interacts with the estrogen receptor α in a distinct manner from estradiol. Mol Cell Endocrinol 142(1):203–214

    Article  CAS  Google Scholar 

  • Hoekstra EJ, Simoneau C (2013) Release of bisphenol A from polycarbonate—a review. Crit Rev Food Sci 53(4):386–402

    Article  CAS  Google Scholar 

  • Hong H, Yang L, Stallcup MR (1999) Hormone-independent transcriptional activation and coactivator binding by novel orphan noclear receptor ERR3. J Biol Chem 274(32):22618–22626

    Article  CAS  Google Scholar 

  • Im J, Loffler FE (2016) Fate of bisphenol A in terrestrial and aquatic environments. Environ Sci Technol 50(16):8403–8416

    Article  CAS  Google Scholar 

  • Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88(3):347–354

    Article  CAS  Google Scholar 

  • Katchy A, Pinto C, Jonsson P, Nguyen-Vu T, Pandelova M, Riu A, Schramm KW, Samarov D, Gustafsson JÅ, Bondesson M, Williams C (2013) Coexposure to phytoestrogens and bisphenol A mimics estrogenic effects in an additive manner. Toxicol Sci 138(1):21–35

    Article  CAS  Google Scholar 

  • Kelly PN, Strasser A (2011) The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ 18(9):1414–1424

    Article  CAS  Google Scholar 

  • Kim HS, Ishizaka M, Kazusaka A, Fujita S (2007) Di-(2-ethylhexyl) phthalate suppresses tamoxifen-induced apoptosis in GH3 pituitary cells. Arch Toxicol 81(1):27–33

    Article  CAS  Google Scholar 

  • Kuiper GGJM, Lemmen JG, Carlsson BO, Corton JC, Safe SH, Saag PTVD, Burg BVD, Gustafsson JÅ (1998) Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology 139(10):4252–4263

    Article  CAS  Google Scholar 

  • LaPensee EW, Tuttle TR, Fox S, Ben-Jonathanet N (2009) Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-α–positive and–negative breast cancer cells. Environ Health Persp 117(2):175–180

    Article  CAS  Google Scholar 

  • LaPensee EW, LaPensee CR, Fox S, Schwemberger S, Afton S, Ben-Jonathanet N (2010) Bisphenol A and estradiol are equipotent in antagonizing cisplatin-induced cytotoxicity in breast cancer cells. Cancer Lett 290(2010):167–173

    Article  CAS  Google Scholar 

  • La Rosa P, Pellegrini M, Totta P, Acconcia F, Marino M (2014) Xenoestrogens alter estrogen receptor (ER) α intracellular levels. PLoS One 9(2):e88961

    Article  CAS  Google Scholar 

  • Lee SY, Ahn BT, Baik SH, Baik SH, Lee BL (1998) Tamoxifen inhibits GH3 cell growth in culture via enhancement of apoptosis. Neurosurgery 43(1):116–123

    Article  CAS  Google Scholar 

  • Lee HR, Hwang KA, Park MA (2012) Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int J Mol Med 29(5):883–890

    CAS  Google Scholar 

  • Li Y, Birnbaumer L, Teng CT (2010) Regulation of ERRα gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: differential molecular mechanisms mediated by G protein-coupled receptor GPR30/GPER-1. Mol Endocrinol 24(5):969–980

    Article  CAS  Google Scholar 

  • Lillo MA, Nichols C, Seagroves TN, Miranda-Carboni GA, Krum SA (2017) Bisphenol A induces Sox2 in ER+ breast cancer stem-like cells. Horm Cancer-US 8(2):90–99

    Article  CAS  Google Scholar 

  • Liu H, Chen F, Zhang L, Zhou Q, Gui S, Wang Y (2016) A novel all-trans retinoic acid derivative 4-amino-2-trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP. Oncol Rep 36(1):333–341

    Article  CAS  Google Scholar 

  • Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, Gillet C, Ellis P, Ryder K, Reid JF, Daidone MG, Pierotti MA, Berns EM, Jansen MPHM, Foekens JA, Delorenzi M, Bontempi G, Piccart MJ, Sotiriou C (2008) Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 9(1):239

    Article  CAS  Google Scholar 

  • Luciani-Torres MG, Moore DH, Goodson IIIWH, Dairkee SH (2014) Exposure to the polyester PET precursor—terephthalic acid induces and perpetuates DNA damage-harboring non-malignant human breast cells. Carcinogenesis 36(1):168–176

    Article  CAS  Google Scholar 

  • Madhavan S, Gusev Y, Singh S, Riggins RB (2015) ERRγ target genes are poor prognostic factors in tamoxifen-treated breast cancer. J Exp Clin Canc Res 34(1):45

    Article  CAS  Google Scholar 

  • Mandlekar S, Yu R, Tan TH, Kong ANT (2000) Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. Cancer Res 60(21):5995–6000

    CAS  Google Scholar 

  • Matsushima A, Kakuta Y, Teramoto T, Koshiba T, Liu X, Okada H, Tokunaga T, Kawabata S, Kimura M, Shimohigashi Y (2007) Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERRγ. J Biochem 142(4):517–524

    Article  CAS  Google Scholar 

  • Mesner PW, Budihardjo II (1997) Kaufmann SH. Chemotherapy-induced apoptosis. Adv Pharmacol 41: 461–499

    Article  CAS  Google Scholar 

  • Michałowicz J (2014) Bisphenol A–sources, toxicity and biotransformation. Environ Toxicol Phar 37(2):738–758

    Article  CAS  Google Scholar 

  • Nigam M, Ranjan V, Srivastava S, Sharma R, Balapure AK (2008) Centchroman induces G0/G1 arrest and caspase-dependent apoptosis involving mitochondrial membrane depolarization in MCF-7 and MDA MB-231 human breast cancer cells. Life Sci 82(11):577–590

    Article  CAS  Google Scholar 

  • Okada H, Tokunaga T, Liu XH, Takayanagi S, Matsushima A, Shimohigashi Y (2008) Direct evidence revealing structural elements essential for the high binding ability of bisphenol A to human estrogen-related receptor-γ. Environ Health Persp 116(1):32–38

    Article  CAS  Google Scholar 

  • Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 62:233–247

    Article  CAS  Google Scholar 

  • Peyrade F, Frenay M, Etienne MC, Ruch F, Guillemare C, Francois E, Namer M, Ferrece JM, Milano G (1996) Age-related difference in tamoxifen disposition. Clin Pharmacol Ther 59(4):401–410

    Article  CAS  Google Scholar 

  • Pfeifer D, Chung YM, Hu MCT (2015) Effects of low-dose bisphenol A on DNA damage and proliferation of breast cells: the role of c-Myc. Environ Health Persp 123(12):1271–1279

    Article  CAS  Google Scholar 

  • Riggins RB, Lan JPJ, Klimach U, Zwart A, Cavalli LR, Haddad BR, Chen L, Gong T, Xuan J, Ethier SP, Clarke R (2008) ERRγ mediates tamoxifen resistance in novel models of invasive lobular breast cancer. Cancer Res 68(21):8908–8917

    Article  CAS  Google Scholar 

  • Schwartz GK, Shah MA (2015) Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 23(36):9408–9421

    Article  CAS  Google Scholar 

  • Song H, Zhang T, Yang P, Li MH, Yang YH, Wang YY, Du J, Pan KJ, Zhang K (2015) Low doses of bisphenol A stimulate the proliferation of breast cancer cells via ERK1/2/ERRγ signals. Toxicol in Vitro 30(1):521–528

    Article  CAS  Google Scholar 

  • Suzuki T, Miki Y, Moriya T, Shimada N, Ishida T, Hirakawa H, Ohuchi N, Sasano H (2004) Estrogen-related receptor α in human breast carcinoma as a potent prognostic factor. Cancer Res 64(13):4670–4676

    Article  CAS  Google Scholar 

  • Thiantanawat A, Long BJ, Brodie AM (2003) Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. Cancer Res 63(22):8037–8050

    CAS  Google Scholar 

  • Vandenberg LN, Maffini MV, Sonnenschein C, Rubin S, Soto AM (2009) Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 30(1):75–95

    Article  CAS  Google Scholar 

  • Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJR, Schoenfelder G (2010) Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Persp 118(8):1055–1070

    Article  CAS  Google Scholar 

  • Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Lee DH, Shioda T, Soto AM, Saal FS, Welshons WV, Zoeller RT, Myers JP (2012) Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 33(3):378–455

    Article  CAS  Google Scholar 

  • Wang Z, Liu HY, Liu SJ (2017) Low-dose bisphenol A exposure: a seemingly instigating carcinogenic effect on breast cancer. Adv Sci 4(2):1600248

    Article  CAS  Google Scholar 

  • Wetherill YB, Akingbemi BT, Kanno J, McLachlan JA, Nadal A, Sonnenschein C, Watson CS, Zoeller RT, Belcher SM (2007) In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol 24(2):178–198

    Article  CAS  Google Scholar 

  • Wu J, Jiang Y, Cao W, Li X, Xie C, Geng S (2018) mir-19 targeting of pten mediates butyl benzyl phthalate-induced proliferation in both ER(+) and ER(-) breast cancer cells. Toxicol Lett 295:124–133

    Article  CAS  Google Scholar 

  • Xu ZX, Liu J, Gu LP, Ma XD, Huang B, Pan XJ (2016) Research progress on the reproductive and non-reproductive endocrine tumors by estrogen-related receptors. J Steroid Biochem Mol Biol 158:22–30

    Article  CAS  Google Scholar 

  • Xu ZX, Liu J, Gu LP, Huang B, Pan XJ (2017a) Biological effects of xenoestrogens and the functional mechanisms via genomic and nongenomic pathways. Environ Rev 25(3):306–322

    Article  CAS  Google Scholar 

  • Xu ZX, Liu J, Wu XH, Huang B, Pan XJ (2017b) Nonmonotonic responses to low doses of xenoestrogens: a review. Environ Res 155:199–207

    Article  CAS  Google Scholar 

  • Xu ZX, Huang B, Liu J, Wu XH, Luo N, Wang XX, Zheng ZY, Pan XJ (2018) Combinatorial anti-proliferative effects of tamoxifen and naringenin: the role of four estrogen receptor subtypes. Toxicology 410:231–246

    Article  CAS  Google Scholar 

  • Yeh WL, Lin HY, Wu HM, Chen DR (2014) Combination treatment of tamoxifen with risperidone in breast cancer. PLoS One 9(6):e98805

    Article  CAS  Google Scholar 

  • Zuccarello P, Oliveri CG, Cavallaro F, Copat C, Cristaldi A, Fiore M, Ferrante M (2018) Implication of dietary phthalates in breast cancer: a systematic review. Food Chem Toxicol 118:667–674

    Article  CAS  Google Scholar 

Download references

Funding

This project was sponsored by the National Natural Science Foundation of China (Grant no. 21567014) and the Yunnan Province Scholarship Award (Grant no. 1319880239).

Author information

Authors and Affiliations

  1. Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, 650500, China

    Bin Huang, Nao Luo, Xinhao Wu, Zhixiang Xu, Xiaoxia Wang & Xuejun Pan

Authors
  1. Bin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nao Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinhao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhixiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xuejun Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhixiang Xu or Xuejun Pan.

Additional information

Responsible editor: Philippe Garrigues

Electronic supplementary material

ESM 1

(PDF 68 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, B., Luo, N., Wu, X. et al. The modulatory role of low concentrations of bisphenol A on tamoxifen-induced proliferation and apoptosis in breast cancer cells. Environ Sci Pollut Res 26, 2353–2362 (2019). https://doi.org/10.1007/s11356-018-3780-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-018-3780-6

Keywords

Search

Navigation