{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:46:18Z","timestamp":1760147178704,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T00:00:00Z","timestamp":1673395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wroclaw Medical University","award":["SUBK.D150.22.039"],"award-info":[{"award-number":["SUBK.D150.22.039"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Endocrine-disrupting compounds (EDC) play an important role in the increased incidence of breast cancer (BC). There are some 160 xenoestrogens that may be involved in the development of BC. Much less is known about the influence of xenoestrogens on the effectiveness of the treatment of BC. The aim of this study was to analyze the interaction of metalloestrogens (aluminum and chromium (III)) and drugs used in the treatment of hormone-dependent BC\u2014aromatase inhibitors (AI)\u2014letrozole and exemestane. A cell viability assay, a flow cytometer analysis of apoptosis and cell cycle phases, and protein activity of BAX and Bcl-2 were performed on two human breast cancer cell lines\u2014MCF-7 and MCF-7\/DOX. In MCF-7 cells, the lower concentration of exemestane and higher of letrozole, in combination with metalloestrogens, results in a decrease in the effectiveness of drugs. Additionally, in the MCF-7\/DOX cell line, we observed that the combination of metalloestrogens and AI leads to a decrease in the drug\u2019s effectiveness due to an increase in the viability of breast cancer cells (both concentrations of letrozole and higher concentration of exemestane). In both cell lines, the reduction in the effectiveness of AI, in combination with metalloestrogens, is not related to the influence on the cell cycle. Our results confirm that exposure to metalloestrogens may negatively affect the effectiveness of hormone therapy with AI. Further studies are needed to fully explain the mechanism of these interactions.<\/jats:p>","DOI":"10.3390\/cancers15020457","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T03:40:35Z","timestamp":1673408435000},"page":"457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Effect of Metalloestrogens on the Effectiveness of Aromatase Inhibitors in a Hormone-Dependent Breast Cancer Cell Model"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0363-9208","authenticated-orcid":false,"given":"Kamila","family":"Boszkiewicz","sequence":"first","affiliation":[{"name":"Department of Toxicology, Wroclaw Medical University, Borowska Street 211, 50-556 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Moreira","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211, 50-556 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Sawicka","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Wroclaw Medical University, Borowska Street 211, 50-556 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Szyjka","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211, 50-556 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Piwowar","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Wroclaw Medical University, Borowska Street 211, 50-556 Wroclaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, November 16). Breast Cancer, Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/breast-cancer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","first-page":"207","article-title":"Breast cancer","volume":"16","author":"Jassem","year":"2020","journal-title":"Oncol. Clin. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1002\/ijc.31352","article-title":"Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation","volume":"143","author":"Abubakar","year":"2018","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1001\/jama.2018.19323","article-title":"Breast cancer treatment. A review","volume":"321","author":"Waks","year":"2019","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000499931","article-title":"St. Gallen\/Vienna 2019: A brief of summary of the consensus discussion on the optimal primary breast cancer treatment","volume":"14","author":"Balic","year":"2019","journal-title":"Breast Care"},{"key":"ref_7","unstructured":"(2022, November 16). ESMO Clinical Practice Guidelines: Breast Cancer. Available online: https:\/\/www.esmo.org\/guidelines\/breast-cancer."},{"key":"ref_8","unstructured":"Peters, A., and Tadi, P. Aromatase Inhibitors, StatPearls Publishing. Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK557856\/."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, X., Ha, D., Yoshitake, R., Chan, Y.S., Sadava, D., and Chen, S. (2021). Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168798"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.5604\/01.3001.0014.1542","article-title":"The importance of environmental exposure on selected xenoestrogens in the pathogenesis of breast cancer","volume":"74","author":"Sawicka","year":"2020","journal-title":"Postepy Hig. Med. Dosw."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"526","DOI":"10.26444\/aaem\/124165","article-title":"The impact of xenoestrogens on effectiveness of treatment for hormone-dependent breast cancer\u2013current state of knowledge and perspectives for research","volume":"27","author":"Boszkiewicz","year":"2020","journal-title":"Ann Agric Environ Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S0278-6915(02)00018-2","article-title":"The endocrine disrupters: A major medical challenge","volume":"40","year":"2002","journal-title":"Food Chem. Toxicol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1016\/j.tjog.2015.11.003","article-title":"Impact of low concentrations of phthalates on the effects of 17\u03b2-estradiol in MCF-7 breast cancer cells","volume":"55","author":"Chen","year":"2016","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.4149\/endo_2013_04_189","article-title":"Bisfenol A alone and in combination with estradiol modulates cell cycle and apoptosis-related proteins and genes in MCF-7 cells","volume":"47","author":"Mlynarcikova","year":"2013","journal-title":"Endocr. Regul."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1600248","DOI":"10.1002\/advs.201600248","article-title":"Low-dose bisphenol A exposure: A seemingly instigating carcinogenic effect in breast cancer","volume":"4","author":"Wang","year":"2016","journal-title":"Adv. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0048-9697(03)00190-6","article-title":"Evaluation of estrogenicity of major heavy metals","volume":"312","author":"Choe","year":"2003","journal-title":"Sci. Total Environ."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Eve, L., Fervers, B., Romancer, M.L., and Etienne-Selloum, N. (2020). Exposure to endocrine disrupting chemicals and risk of breast cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239139"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1177\/000313480206800612","article-title":"Genistein inhibits tamoxifen effects on cell proliferation and cell cycle arrest in T47D breast cancer cells","volume":"68","author":"Jones","year":"2002","journal-title":"Am. Surg."},{"key":"ref_19","first-page":"2474","article-title":"Dietary genistein negates the inhibitory effect of tamoxifen on growth of estrogen-dependent human breast cancer (MCF-7) cells implanted in athymic mice","volume":"62","author":"Ju","year":"2002","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1158\/0008-5472.879.65.3","article-title":"Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumour prevention","volume":"65","author":"Liu","year":"2005","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.ejca.2004.12.005","article-title":"The soy isoflavone didzein improves the capacity of tamoxifen to prevent mammary tumours","volume":"41","author":"Constantinou","year":"2005","journal-title":"Eur. J. Cancer."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10549-006-9191-2","article-title":"Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha","volume":"99","author":"Seo","year":"2006","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1093\/carcin\/bgr196","article-title":"Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women","volume":"32","author":"Luciani","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1093\/carcin\/bgs017","article-title":"Low-dose dietary genistein negates the therapeutic effect of tamoxifen in anthymic nude mice","volume":"33","author":"Du","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.chembiol.2017.12.010","article-title":"Metabolomics reveals that dietary xenoestrogens alter cellular metabolism induced by palbociclib\/letrozole combination cancer therapy","volume":"25","author":"Warth","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1289\/ehp.11788","article-title":"Bisphenol A at low nanomolar doses confers chemoresistance in estrogen receptor-\u03b1- positive and -negative breast cancer cells","volume":"117","author":"LaPensee","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.morpho.2016.02.001","article-title":"Aluminium and the human breast","volume":"100","author":"Darbre","year":"2016","journal-title":"Morphologie"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.jinorgbio.2013.07.004","article-title":"Effect of aluminium on migratory and invasive properties of MCF-7 human breast cancer cells in culture","volume":"128","author":"Darbre","year":"2013","journal-title":"J. Inorg. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1039\/C8TX00233A","article-title":"Cell cycle and transmembrane mitochondrial potential analysis after treatment with chromium(III), iron (III), molybdenum (III) or nickel (II) and their mixtures","volume":"8","author":"Terpilowska","year":"2019","journal-title":"Toxicol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"357","DOI":"10.32383\/farmpol\/116118","article-title":"Estrogenowe dzia\u0142anie chromu\u2013wa\u017cny metaloestrogen w modulowaniu szlak\u00f3w endokrynnych","volume":"75","author":"Sawicka","year":"2019","journal-title":"Farm. Pol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Christowitz, C., Davis, T., Isaacs, A., van Niekerk, G., Hattingh, S., and Engelbrecht, A.M. (2019). Mechanisms of doxorubicin-induced drug re-sistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5939-z"},{"key":"ref_32","first-page":"913","article-title":"Human breast cancer MCF-7 cell line contains inherently drug-resistant subclones with distinct genotypic and phenotypic features","volume":"20","author":"Devarajan","year":"2002","journal-title":"Int. J. Oncology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8617","DOI":"10.7314\/APJCP.2014.15.20.8617","article-title":"Roles of the Bcl-2\/BAX ratio, caspase-8 and 9 in resistance of breast cancer cells to paclitaxel","volume":"15","author":"Sharifi","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.taap.2013.03.014","article-title":"Phytoestrogens in menopausal supplements induce ER-dependent cell proliferaton and overcome breast cancer treatment in an in vitro breast cancer model","volume":"269","author":"Smeets","year":"2013","journal-title":"Toxicol. App. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1055\/s-2007-967130","article-title":"Coadministration of the aromatase inhibitor formestane and an isopropanolic extract of black cohosh in a rat model of chemically induced mammary carcinoma","volume":"73","author":"Freudenstein","year":"2007","journal-title":"Planta Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pfeffer, C.M., and Singh, A.T.K. (2018). Apoptosis: A Target for Anticancer Therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020448"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3892\/mmr.2015.3406","article-title":"Synergistic effects of combined treatment with simvastatin and exemestane on MCF-7 human breast cancer cells","volume":"12","author":"Shen","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Urade, R., Chou, C.K., Chou, H.L., Chen, B.H., Wang, T.N., Tsai, E.M., Hung, C.T., Wu, S.J., and Chiu, C.C. (2022). Phthalate derivative DEHP disturbs the antiproliferative effect of camptoth-ecin in human lung cancer cells by attenuating DNA damage and activating Akt\/NF-\u03baB signaling pathway. Environ Toxicol., 17.","DOI":"10.1002\/tox.23686"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chimento, A., De Luca, A., Avena, P., De Amicis, F., Casaburi, I., Sirianni, R., and Pezzi, V. (2022). Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031242"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41571-020-0341-y","article-title":"Targeting apoptosis in cancer therapy","volume":"17","author":"Carneiro","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"111426","DOI":"10.1016\/j.mce.2021.111426","article-title":"Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells","volume":"537","author":"Augusto","year":"2021","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Amaral, C., Borges, M., Melo, S., Silva, E.T., Correia-da-Silva, G., and Teixeira, N. (2012). Apoptosis and Autophagy in Breast Cancer Cells following Exemestane Treatment. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042398"},{"key":"ref_43","first-page":"8037","article-title":"Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens","volume":"63","author":"Thiantanawat","year":"2003","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7440","DOI":"10.1074\/jbc.271.13.7440","article-title":"Proapoptotic protein Bax heterodimerizes with Bcl2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH1 and BH2","volume":"271","author":"Zha","year":"1996","journal-title":"J. Biol. Chem."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/2\/457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:06:32Z","timestamp":1760119592000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/2\/457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cancers15020457"],"URL":"https:\/\/doi.org\/10.3390\/cancers15020457","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}