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

Abstract

A significant percentage (~30%) of estrogen receptor-α (ERα)-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 ERα-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 ERα 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 (MCF7NaAsIII) 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 ERα, CpG hypermethylation of estrogen receptor 1 (ESR1) and BRCA1, and the increased expression of FOLR1. These cumulative data support the hypothesis that exposure to AsIII may contribute to reducing the efficacy of endocrine therapy against ERα-positive breast tumors by hampering the expression of ERα and BRCA1 via CpG methylation, respectively of ESR1 and BRCA1.

ELOVL2: a novel tumor suppressor attenuating tamoxifen resistance in breast cancer

“…1a). Among highly altered genes, ESR1 (Δβ = 0.35), MAGED1 (Δβ = 0.3), and RASAL1(Δβ = 0.36) were listed, alteration in methylation of which in TamR cells has been previously known [26][27][28], indicating the reliability of MCF-7/TamR cells developed in the current study. The microarray data were also veri ed by examining the expression of ve randomly selected genes from the highly altered genes via qPCR.…”

<p>ERα, A Key Target for Cancer Therapy: A Review</p>

“…[7][8][9] Emerging evidence shows that the activation of ERs is highly associated with cancer formation and metastasis, [10][11][12] extracellular matrix (ECM) remodeling 2,13 and drug resistance. [14][15][16][17] Here, we focus on providing a comprehensive understanding of ERα. We hope this will help doctors to find more effective ways to treat ERα-related cancers.…”

Inorganic arsenic promotes luminal to basal transition and metastasis of breast cancer

“…Like estradiol itself, iAs is known to promote the internalization and degradation of the estrogen receptor. [12][13][14][15] In contrast to these acute effects, the impact of more prolonged exposures to iAs is less clear, despite this being a more likely scenario for environmental exposures through drinking water. In the current study, we sought to determine if prolonged exposure to iAs persistently and/ or reversibly changes estrogen receptor expression and function at the molecular and functional levels.…”

“…iAs has a well‐documented acute effect as a weak pseudo‐estrogen. Like estradiol itself, iAs is known to promote the internalization and degradation of the estrogen receptor 12‐15 . In contrast to these acute effects, the impact of more prolonged exposures to iAs is less clear, despite this being a more likely scenario for environmental exposures through drinking water.…”