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
AffiliationUniv Arizona, Dept Nutr Sci
Univ Arizona, Canc Biol Grad Interdisciplinary Program
MetadataShow full item record
PublisherSPANDIDOS PUBL LTD
CitationSelmin, 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
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AbstractA 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.
Note6 month embargo; published online: 15 January 2019
VersionFinal published version
SponsorsNational Cancer Institute of the National Institutes of Health [U54CA143924]; Cancer Biology Training Grant [T32CA009213]; Cancer Center Support Grant [P30CA023074]
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