The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA.
Cancer Biology Graduate Interdisciplinary Program, The University of Arizona, Tucson, AZ 85724, USA.
Int J Oncol. 2019 Mar;54(3):869-878. doi: 10.3892/ijo.2019.4687. Epub 2019 Jan 15.
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.
约 30%的雌激素受体-α（ERα）阳性肿瘤对内分泌治疗产生耐药性；然而，导致这种耐药性的机制在很大程度上尚不清楚。通过食物和受污染的水慢性暴露于砷已与多种肿瘤的发病率增加和长期健康并发症相关联。临床前和人群研究表明，砷暴露可能会干扰内分泌调节并增加乳腺癌发生的风险。在这项研究中，我们研究了亚砷酸钠（NaAsIII）在 ERα 阳性乳腺癌细胞中的体外暴露和在乳腺肿瘤异种移植物中的作用。结果表明，急性（4 天内）和长期（10 天至 7 周）的体外暴露于环境相关剂量会降低乳腺癌 1（BRCA1）和 ERα 的表达，同时导致细胞周期蛋白 D1（CCND1）和叶酸受体 1（FOLR1）的获得，以及亚甲基四氢叶酸还原酶（MTHFR）的表达丧失。此外，长期暴露于 NaAsIII 会诱导 MCF7 细胞的增殖并损害其对他莫昔芬（TAM）的反应。NaAsIII 的体外暴露会诱导 BRCA1 的 CpG 甲基化，从而导致 DNA 甲基转移酶 1（DNMT1）的募集增加和 BRCA1 基因处 RNA 聚合酶 II（PolII）的丧失。将 NaAsIII 预处理的 MCF7 细胞（MCF7NaAsIII）异种移植到裸鼠的乳腺脂肪垫中，与对照 MCF7 细胞相比，产生了更大的肿瘤体积，并且对 TAM 的耐药性更强，同时伴随着 BRCA1 和 ERα 的表达降低、雌激素受体 1（ESR1）和 BRCA1 的 CpG 过度甲基化以及 FOLR1 的表达增加。这些累积数据支持这样一种假说，即暴露于 AsIII 可能通过 CpG 甲基化分别干扰 ERα 和 BRCA1 的表达，从而降低内分泌疗法对 ERα 阳性乳腺癌的疗效。
