Email the author Potential interference of aluminum chlorohydrate with estrogen receptor signaling in breast cancer cells
Abstract
Aluminum salts are widely used as the active antiperspirant in underarm cosmetic. Experimental observations indicate that its long term application may correlate with breast cancer development and progression. This action is proposed to be attributed, among others, to aluminum possible estrogen-like activities. In this study we showed that aluminum, in the form of aluminum chlorohydrate (ACH), caused increase in estrogen receptor alpha (ERα) protein levels, in ERα-positive MCF-7 cells. This effect was accompanied by moderate activation of Estrogen Response Elements (ERE)-driven reporter gene expression and 20%-50% increase in certain estrogen responsive, ERE-independent genes expression. Genes affected were ERα, p53, cyclin D1, and c-fos, crucial regulators of breast cancer development and progression. ACH-induced genes expression was eliminated in the presence of the estrogen antagonist: ICI 182780, in MCF-7 cells, whereas it was not observed in ERα-negative MDA-MB-231 breast cancer cells, indicating aluminum interference with estrogen signaling. Moreover, ACH caused increase in the perinuclear localization of estrogen receptor alpha in MCF-7 breast cancer cells and increase in the mitochondrial Bcl-2 protein, possibly affecting receptors-mediated mitochondrial actions and mitochondrial-dependent apoptosis. ACH-induced perinuclear localization of estrogen receptor beta was also observed in MDA-MB-231. Our findings indicate that aluminum actions on estrogen receptors protein level and subcellular localization possibly affect receptors-mediated actions and thus, aluminum interference with estrogen signaling.
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References
Acconcia F, Fiocchetti M & Marino M 2017 Xenoestrogen regulation of ERalpha/ERbeta balance in hormone-associated cancers. Mol Cell Endocrinol 457 3-12
Al-Mehdi A-B, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, Pastukh VV, Alexeyev MF & Gillespie MN 2012 Perinuclear Mitochondrial Clustering Creates an Oxidant-Rich Nuclear Domain Required for Hypoxia-Induced Transcription. Science signaling 5 ra47
Bakir A & Darbre PD 2015 Effect of aluminium on migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells in culture. J Inorg Biochem 152 180-185
Berger CE, Qian Y, Liu G, Chen H & Chen X 2012 p53, a target of estrogen receptor (ER) alpha, modulates DNA damage-induced growth suppression in ER-positive breast cancer cells. J Biol Chem 287 30117-30127
Bjornstrom L & Sjoberg M 2005 Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19 833-842
Bondesson M, Hao R, Lin CY, Williams C & Gustafsson JA 2015 Estrogen receptor signaling during vertebrate development. Biochim Biophys Acta 1849 142-151
Bradford MM 1976 A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72 248-254
Byrne C, Divekar SD, Storchan GB, Parodi DA & Martin MB 2013 Metals and breast cancer. J Mammary Gland Biol Neoplasia 18 63-73
Castro-Rivera E, Samudio I & Safe S 2001 Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. J Biol Chem 276 30853-30861
Chang EC, Frasor J, Komm B & Katzenellenbogen BS 2006 Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology 147 4831-4842
Chen JQ, Cammarata PR, Baines CP & Yager JD 2009 Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications. Biochim Biophys Acta 1793 1540-1570
Chen JQ, Eshete M, Alworth WL & Yager JD 2004 Binding of MCF‐7 cell mitochondrial proteins and recombinant human estrogen receptors α and β to human mitochondrial dna estrogen response elements. Journal of Cellular Biochemistry 93 358-373
Chen JQ & Yager JD 2004 Estrogen's effects on mitochondrial gene expression: mechanisms and potential contributions to estrogen carcinogenesis. Ann N Y Acad Sci 1028 258-272
Chen Z, Wang Y, Warden C & Chen S 2015 Cross-talk between ER and HER2 regulates c-MYC-mediated glutamine metabolism in aromatase inhibitor resistant breast cancer cells. J Steroid Biochem Mol Biol 149 118-127
Childs BG, Baker DJ, Kirkland JL, Campisi J & van Deursen JM 2014 Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15 1139-1153
Corain B, Bombi GG, Tapparo A, Nicolini M, Zatta P, Perazzolo M & Favarato M 1990 Alzheimer's disease and aluminum toxicology. Environ Health Perspect 89 233-235
Cotrim CZ, Fabris V, Doria ML, Lindberg K, Gustafsson JA, Amado F, Lanari C & Helguero LA 2013 Estrogen receptor beta growth-inhibitory effects are repressed through activation of MAPK and PI3K signalling in mammary epithelial and breast cancer cells. Oncogene 32 2390-2402
Darbre PD 2005 Aluminium, antiperspirants and breast cancer. J Inorg Biochem 99 1912-1919
Darbre PD 2006 Metalloestrogens: an emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast. J Appl Toxicol 26 191-197
Darbre PD 2009 Underarm antiperspirants/deodorants and breast cancer. Breast Cancer Res 11 Suppl 3 S5
Darbre PD 2016 Aluminium and the human breast. Morphologie 100 65-74
Darbre PD, Bakir A & Iskakova E 2013a Effect of aluminium on migratory and invasive properties of MCF-7 human breast cancer cells in culture. J Inorg Biochem 128 245-249
Darbre PD & Charles AK 2010 Environmental oestrogens and breast cancer: evidence for combined involvement of dietary, household and cosmetic xenoestrogens. Anticancer Res 30 815-827
Darbre PD, Mannello F & Exley C 2013b Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology. J Inorg Biochem 128 257-261
Dorea JG 2015 Exposure to mercury and aluminum in early life: developmental vulnerability as a modifying factor in neurologic and immunologic effects. Int J Environ Res Public Health 12 1295-1313
Duan R, Porter W & Safe S 1998 Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology 139 1981-1990
Exley C, Charles LM, Barr L, Martin C, Polwart A & Darbre PD 2007 Aluminium in human breast tissue. J Inorg Biochem 101 1344-1346
Gherardi RK, Aouizerate J, Cadusseau J, Yara S & Authier FJ 2016 Aluminum adjuvants of vaccines injected into the muscle: Normal fate, pathology and associated disease. Morphologie 100 85-94
Gu G, Barone I, Gelsomino L, Giordano C, Bonofiglio D, Statti G, Menichini F, Catalano S & Ando S 2012 Oldenlandia diffusa extracts exert antiproliferative and apoptotic effects on human breast cancer cells through ERalpha/Sp1-mediated p53 activation. J Cell Physiol 227 3363-3372
Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M, et al. 2007 Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiological Reviews 87 905-931
Jaber BM, Gao T, Huang L, Karmakar S & Smith CL 2006 The pure estrogen receptor antagonist ICI 182,780 promotes a novel interaction of estrogen receptor-alpha with the 3',5'-cyclic adenosine monophosphate response element-binding protein-binding protein/p300 coactivators. Mol Endocrinol 20 2695-2710
Jia M, Dahlman-Wright K & Gustafsson JA 2015 Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab 29 557-568
Johnston SJ & Cheung KL 2010 Fulvestrant - a novel endocrine therapy for breast cancer. Curr Med Chem 17 902-914
Kawahara M & Kato-Negishi M 2011 Link between Aluminum and the Pathogenesis of Alzheimer's Disease: The Integration of the Aluminum and Amyloid Cascade Hypotheses. Int J Alzheimers Dis 2011 276393
La Rosa P, Pellegrini M, Totta P, Acconcia F & Marino M 2014 Xenoestrogens alter estrogen receptor (ER) alpha intracellular levels. PLoS One 9 e88961
Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM & Corbo L 2011 Cracking the estrogen receptor's posttranslational code in breast tumors. Endocr Rev 32 597-622
Levin ER 2009 Membrane oestrogen receptor alpha signalling to cell functions. J Physiol 587 5019-5023
Liao TL, Tzeng CR, Yu CL, Wang YP & Kao SH 2015 Estrogen receptor‐β in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis. Annals of the New York Academy of Sciences 1350 52-60
Liu W, Ip MM, Podgorsak MB & Das GM 2009 Disruption of estrogen receptor alpha-p53 interaction in breast tumors: a novel mechanism underlying the anti-tumor effect of radiation therapy. Breast Cancer Res Treat 115 43-50
Liu W, Konduri SD, Bansal S, Nayak BK, Rajasekaran SA, Karuppayil SM, Rajasekaran AK & Das GM 2006 Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function. J Biol Chem 281 9837-9840
Lonergan T, Bavister B & Brenner C 2007 Mitochondria in stem cells. Mitochondrion 7 289-296
Mannello F, Tonti GA & Darbre PD 2009 Concentration of aluminium in breast cyst fluids collected from women affected by gross cystic breast disease. J Appl Toxicol 29 1-6
Mannello F, Tonti GA, Medda V, Simone P & Darbre PD 2011 Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients. J Appl Toxicol 31 262-269
Marino M, Pellegrini M, La Rosa P & Acconcia F 2012 Susceptibility of estrogen receptor rapid responses to xenoestrogens: Physiological outcomes. Steroids 77 910-917
Martinez-Outschoorn UE, Pavlides S, Sotgia F & Lisanti MP 2011 Mitochondrial biogenesis drives tumor cell proliferation. Am J Pathol 178 1949-1952
Maya S, Prakash T, Madhu KD & Goli D 2016 Multifaceted effects of aluminium in neurodegenerative diseases: A review. Biomed Pharmacother 83 746-754
McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A & Burgess A 2014 Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 13 1400-1412
Mold M, Shardlow E & Exley C 2016 Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations. Sci Rep 6 31578
Okatsu K, Saisho K, Shimanuki M, Nakada K, Shitara H, Sou YS, Kimura M, Sato S, Hattori N, Komatsu M, et al. 2010 p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria. Genes Cells 15 887-900
Osborne CK, Wakeling A & Nicholson RI 2004 Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer 90 Suppl 1 S2-6
Pasqualini JR 2004 The selective estrogen enzyme modulators in breast cancer: a review. Biochim Biophys Acta 1654 123-143
Perillo B, Sasso A, Abbondanza C & Palumbo G 2000 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol 20 2890-2901
Pinzone JJ, Stevenson H, Strobl JS & Berg PE 2004 Molecular and cellular determinants of estrogen receptor alpha expression. Mol Cell Biol 24 4605-4612
Porter W, Saville B, Hoivik D & Safe S 1997 Functional Synergy between the Transcription Factor Sp1 and the Estrogen Receptor. Molecular Endocrinology 11 1569-1580
Psarra AM, Hermann S, Panayotou G & Spyrou G 2009 Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-kappaB modulates glucocorticoid receptor and NF-kappaB signalling in HEK-293 cells. Biochem J 422 521-531
Psarra AM & Sekeris CE 2008 Nuclear receptors and other nuclear transcription factors in mitochondria: regulatory molecules in a new environment. Biochim Biophys Acta 1783 1-11
Psarra AM & Sekeris CE 2011 Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta 1813 1814-1821
Psarra AM, Solakidi S, Trougakos IP, Margaritis LH, Spyrou G & Sekeris CE 2005 Glucocorticoid receptor isoforms in human hepatocarcinoma HepG2 and SaOS-2 osteosarcoma cells: presence of glucocorticoid receptor alpha in mitochondria and of glucocorticoid receptor beta in nucleoli. Int J Biochem Cell Biol 37 2544-2558
Qian Y & Chen X 2013 Senescence regulation by the p53 protein family. Methods Mol Biol 965 37-61
Raffetto JD, Leverkus M, Park HY & Menzoian JO 2001 Synopsis on cellular senescence and apoptosis. J Vasc Surg 34 173-177
Saceda M, Lippman ME, Chambon P, Lindsey RL, Ponglikitmongkol M, Puente M & Martin MB 1988 Regulation of the estrogen receptor in MCF-7 cells by estradiol. Mol Endocrinol 2 1157-1162
Sana M & Malik HJ 2015 Current and emerging breast cancer biomarkers. J Cancer Res Ther 11 508-513
Sappino AP, Buser R, Lesne L, Gimelli S, Bena F, Belin D & Mandriota SJ 2012 Aluminium chloride promotes anchorage-independent growth in human mammary epithelial cells. J Appl Toxicol 32 233-243
Sayeed A, Konduri SD, Liu W, Bansal S, Li F & Das GM 2007 Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res 67 7746-7755
Tecalco-Cruz AC & Ramirez-Jarquin JO 2017 Mechanisms that Increase Stability of Estrogen Receptor Alpha in Breast Cancer. Clin Breast Cancer 17 1-10
Wang C, Mayer JA, Mazumdar A, Fertuck K, Kim H, Brown M & Brown PH 2011 Estrogen induces c-myc gene expression via an upstream enhancer activated by the estrogen receptor and the AP-1 transcription factor. Mol Endocrinol 25 1527-1538
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