The Aryl Hydrocarbon Receptor Agonists Reactivate Line-1 Retrotransposon In Breast Cancer Cells

MIRET N; PONTILLO C; COCCA C; ZAPPIA C D; CHAPPINI F; MONCZOR F; ZARATE N; LASAGNA M; RANDI A

Mar del Plata

Congreso; Reunion Conjunta de Sociedades de Biociencias: LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC), SAIB, SAI, SAA, SAB, SAB, SAFE, SAFIS, SAH, SAP.; 2017

Sociedad Argentina de Investigación Clínica (SAIC)

Breast cancer is the most common cancer worldwide in womenand Argentina is the second country of America with the highestmortality rate. Epigenetic changes are more frequent in breastcancer cells than genetic mutations. These alterations affect retrotransposonslike the long interspersed nuclear element 1 (LINE-1),which is highly activated in breast tumors. Environmental pollutantsligands of aryl hydrocarbon receptor (AhR) can induce the activationof LINE-1 and epithelial to mesenchymal transition, through thetransforming growth factor-β1 (TGF-β1)/Smad signaling pathway.AhR is a transcription factor that modulates processes such as apoptosis,proliferation and migration. We worked with environmentaldoses of two weak ligands of the AhR: the organochlorine pesticidehexachlorobenzene (HCB) and the organophosphate chlorpyrifos(CPF). Our aim was to study the effect of these pesticides on LINE-1expression and to elucidate whether the mechanism of action is relatedto the interaction AhR/TGF-β1, in the human breast cancer cellline MDA-MB-231 (- estrogen receptor α). We have reported thatHCB (0.005, 0.05, 0.5 y 5 μM) activates the AhR/c-Src signaling,which subsequently induces the TGF-β1/Smad pathway, promotingMDA-MB-231 cell migration and invasion. Our results showed thatLINE-1 mRNA levels, evaluated by RT-qPCR, were enhanced at0.005 μM HCB (p<0.01), but reduced at 5 μM HCB (p<0.05) after 24h. On the other hand, CPF (0.05, 0.5, 5 y 50 μM) increased LINE-1mRNA content after 48 h (p<0.01). Western blot results showed thatCPF (0.5 μM) enhanced AhR protein expression (p<0.05) at 24 h,as well as c-Src (p<0.05) and Smad 2/3 (p<0.01) phosphorylationafter 15 and 30 min. In conclusion, we demonstrated that these pesticidesmodulate LINE-1 expression in MDA-MB-231, depending onthe dose and the time of exposure. These findings could be linkedto alterations previously observed in process like breast cancer cellproliferation, migration or invasion.