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    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

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    Author
    Selmin, Ornella I
    Donovan, Micah G
    Skovan, Bethany
    Paine-Murieta, Gillian D
    Romagnolo, Donato F
    Affiliation
    Univ Arizona, Dept Nutr Sci
    Univ Arizona, Canc Biol Grad Interdisciplinary Program
    Issue Date
    2019-03-01
    Keywords
    arsenic
    estrogen receptor
    BRCA1
    epigenetics
    tamoxifen
    breast cancer
    
    Metadata
    Show full item record
    Publisher
    SPANDIDOS PUBL LTD
    Citation
    Selmin, O.I., Donovan, M.G., Skovan, B., Paine‑Murieta, G.D., & Romagnolo, D.F. (2019). 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, 54, 869-878. https://doi.org/10.3892/ijo.2019.4687
    Journal
    INTERNATIONAL JOURNAL OF ONCOLOGY
    Rights
    © Selmin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    A significant percentage (similar to 30%) of estrogen receptor- (ER)-positive tumors become refractory to endocrine therapies; however, the mechanisms responsible for this resistance remain largely unknown. Chronic exposure to arsenic through foods and contaminated water has been linked to an increased incidence of several tumors and long-term health complications. Preclinical and population studies have indicated that arsenic exposure may interfere with endocrine regulation and increase the risk of breast tumorigenesis. In this study, we examined the effects of sodium arsenite (NaAsIII) exposure in ER-positive breast cancer cells in vitro and in mammary tumor xenografts. The results revealed that acute (within 4 days) and long-term (10 days to 7 weeks) in vitro exposure to environmentally relevant doses reduced breast cancer 1 (BRCA1) and ER expression associated with the gain of cyclin D1 (CCND1) and folate receptor 1 (FOLR1), and the loss of methylenetetrahydrofolate reductase (MTHFR) expression. Furthermore, long-term exposure to NaAsIII induced the proliferation and compromised the response of MCF7 cells to tamoxifen (TAM). The in vitro exposure to NaAsIII induced BRCA1 CpG methylation associated with the increased recruitment of DNA methyltransferase 1 (DNMT1) and the loss of RNA polymerase II (PolII) at the BRCA1 gene. Xenografts of NaAsIII-preconditioned MCF7 cells (MCF7NaAs(III)) into the mammary fat pads of nude mice produced a larger tumor volume compared to tumors from control MCF7 cells and were more refractory to TAM in association with the reduced expression of BRCA1 and ER, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to As-III may contribute to reducing the efficacy of endocrine therapy against ER-positive breast tumors by hampering the expression of ER and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.
    Note
    6 month embargo; published online: 15 January 2019
    ISSN
    1791-2423
    PubMed ID
    30664189
    DOI
    10.3892/ijo.2019.4687
    Version
    Final published version
    Sponsors
    National Cancer Institute of the National Institutes of Health [U54CA143924]; Cancer Biology Training Grant [T32CA009213]; Cancer Center Support Grant [P30CA023074]
    Additional Links
    https://www.spandidos-publications.com/ijo/54/3/869/abstract
    ae974a485f413a2113503eed53cd6c53
    10.3892/ijo.2019.4687
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