Epigenetic changes induced by pesticide exposure reactivate LINE-1 retrotransposon in breast cancer and mammary epithelial cells

NOELIA MIRET; DANIEL ZAPPIA; GABRIELA ALTAMIRANO; CAROLINA PONTILLO; LORENA ZÁRATE; AYELÉN GÓMEZ; MARIANELA LASAGNA; CLAUDIA COCCA; LAURA KASS; FEDERICO MONCZOR; ANDREA RANDI

Buenos Aires

Congreso; Buenos Aires Breast Cancer Symposium BA-BCS 2021; 2021

Edith Kordon, Claudia Lanari

 Expression of long interspersed nuclear element-1 (LINE-1) isreactivated during breast cancer initiation and progression. Strong ligands ofaryl hydrocarbon receptor (AhR) activate LINE-1 through the transforming growthfactor-β1 (TGF-β1)/Smad pathway. Studies have linked breast cancer risk withpesticide exposure, including hexachlorobenzene (HCB) and chlorpyrifos (CPF),both weak AhR ligands which promote alterations in mammary gland and tumorgrowth in animal models. We examined the pesticides action on LINE-1 reactivationin MDA-MB-231 breast cancer cells and NMuMG epithelial breast cells, and weevaluated the role of TGF-β1 and AhR. Results show that 0.5 μM CPF and 0.005 μMHCB reduced the methylation of the 5´-UTR of LINE-1 and increased LINE-1 mRNAexpression via Smad and AhR signaling in MDA-MB-231. Besides, 5 μM CPF and 0.005 μM HCB heighten ORF1p nuclear import,the protein encoded by LINE-1, through TGF-β1/Smad and stimulate DNA double-strandbreaks. Disturbingly, 5 μM CPF and 0.005 μM HCB also enhanced LINE-1 mRNAlevels in NMuMG cells. CPF effect was through AhR and TGF-β1, while HCB actiondepends only of AhR. In addition, both pesticides increased ORF1p expressionand nuclear localization. In conclusion, HCB and CPF induce LINE-1reactivation, not only in breast cancer cells but also in epithelial mammarycells, supporting the idea that pesticide exposure could promote epigeneticchanges, contributing to cell transformation and tumorigenesis in breast cancer.<!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073732485 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin-top:0cm;margin-right:0cm;margin-bottom:8.0pt;margin-left:0cm;line-height:107%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-fareast-language:EN-US;}p.Normal1, li.Normal1, div.Normal1{mso-style-name:Normal1;mso-style-unhide:no;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Arial",sans-serif;mso-fareast-font-family:Arial;mso-fareast-language:ES-AR;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:11.0pt;mso-ansi-font-size:11.0pt;mso-bidi-font-size:11.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-fareast-language:EN-US;}.MsoPapDefault{mso-style-type:export-only;margin-bottom:8.0pt;line-height:107%;}size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}<!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:-536870145 1107305727 0 0 415 0;}@font-face{font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;mso-font-charset:0;mso-generic-font-family:swiss;mso-font-pitch:variable;mso-font-signature:-536859905 -1073732485 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";mso-ansi-language:ES;mso-fareast-language:ES;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-size:10.0pt;mso-ansi-font-size:10.0pt;mso-bidi-font-size:10.0pt;font-family:"Calibri",sans-serif;mso-ascii-font-family:Calibri;mso-hansi-font-family:Calibri;mso-bidi-font-family:Calibri;}size:612.0pt 792.0pt;margin:70.85pt 3.0cm 70.85pt 3.0cm;mso-header-margin:36.0pt;mso-footer-margin:36.0pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}