AhR ligands reactivate LINE-1 retrotransposon in triple-negative breast cancer cells MDA-MB-231 and non-tumorigenic mammary epithelial cells NMuMG

被引：12

作者：

Miret, Noelia ^{[1
]}

Daniel Zappia, C. ^{[2
]}

Altamirano, Gabriela ^{[3
]}

Pontillo, Carolina ^{[1
]}

Zarate, Lorena ^{[1
]}

Gomez, Ayelen ^{[3
]}

Lasagna, Marianela ^{[4
]}

Cocca, Claudia ^{[4
]}

Kass, Laura ^{[3
]}

Monczor, Federico ^{[2
]}

Randi, Andrea ^{[1
]}

机构：

[1] Univ Buenos Aires, Fac Med, Dept Bioquim Humana, Lab Efectos Biol Contaminantes Ambientales, Paraguay 2155,5to Piso, RA-1121 Buenos Aires, DF, Argentina

[2] Univ Buenos Aires, Fac Farm & Bioquim, Inst Invest Farmacol UBA CONICET, Lab Farmacol Receptores, Junin 954, RA-1113 Buenos Aires, DF, Argentina

[3] Univ Nacl Litoral, Fac Bioquim & Ciencias Biol, ISAL, Catedra Patol Humana,CONICET, Ciudad Univ UNL, RA-3000 Santa Fe, Argentina

[4] Univ Buenos Aires, Fac Farm & Bioquim, Dept Fis Matemat, Lab Radioisotopos, Junin 954, RA-1113 Buenos Aires, DF, Argentina

来源：

BIOCHEMICAL PHARMACOLOGY | 2020年 / 175卷

关键词：

Hexachlorobenzene; Chlorpyrifos; Breast cancer; Aryl hydrocarbon receptor; Long interspersed nuclear element-1; ARYL-HYDROCARBON RECEPTOR; LONG INTERSPERSED ELEMENT-1; DOUBLE-STRAND BREAKS; ORGANOCHLORINE PESTICIDES; ESTROGEN-RECEPTOR; SIGNALING PATHWAYS; PRENATAL EXPOSURE; SERUM-LEVELS; HEXACHLOROBENZENE; EXPRESSION;

D O I：

10.1016/j.bcp.2020.113904

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Breast cancer is the most common cancer type in females worldwide. Environmental exposure to pesticides affecting hormonal homeostasis does not necessarily induce DNA mutations but may influence gene expression by disturbances in epigenetic regulation. Expression of long interspersed nuclear element-1 (LINE-1) has been associated with tumorigenesis in several cancers. In nearly all somatic cells, LINE-1 is silenced by DNA methylation in the 5 ''UTR and reactivated during disease initiation and/or progression. Strong ligands of aryl hydrocarbon receptor (AhR) activate LINE-1 through the transforming growth factor-beta 1 (TGF-beta 1)/Smad pathway. Hexachlorobenzene (HCB) and chlorpyrifos (CPF), both weak AhR ligands, promote cell proliferation and migration in breast cancer cells, as well as tumor growth in rat models. In this context, our aim was to examine the effect of these pesticides on LINE-1 expression and ORF1p localization in the triple-negative breast cancer cell line MDA-MB-231 and the non-tumorigenic epithelial breast cell line NMuMG, and to evaluate the role of TGF-beta 1 and AhR pathways. Results show that 0.5 mu M CPF and 0.005 mu M HCB increased LINE-1 mRNA expression through Smad and AhR signaling in MDA-MB-231. In addition, the methylation of the first sites in 5 ''UTR of LINE-1 was reduced by pesticide exposure, although the farther sites remained unaffected. Pesticides modulated ORF1p localization in MDA-MB-231: 0.005 mu M HCB and 50 mu M CPF increased nuclear translocation, while both induced cytoplasmic retention at 0.5 and 5 mu M. Moreover, both stimulated double-strand breaks, enhancing H2AX phosphorylation, coincidentally with ORF1p nuclear localization. In NMuMG similar results were observed, since they heighten LINE-1 mRNA levels. CPF effect was through AhR and TGF-beta 1 signaling, whereas HCB action depends only of AhR. In addition, both pesticides increase ORF1p expression and nuclear localization. Our results provide experimental evidence that HCB and CPF exposure modify LINE-1 methylation levels and induce LINE-1 reactivation, suggesting that epigenetic mechanisms could contribute to pesticide-induced breast cancer progression.

引用

页数：14