Emerging role of AhR / c-Srcsignaling in breast cancer cell migration induced by tumor acidosis

MIRET NOELIA ; ZÁRATE LORENA V; ERRA DÍAZ FERNANDO; PONTILLO CAROLINA A; CEBALLOS LEANDRO; CHIAPPINI FLORENCIA; GEFFNER JORGE; RANDI ANDREA S

Congreso; Buenos Aires Breast Cancer Symposium BA-BCS 2020; 2021

Acidosisis an important factor on tumor development, but little is known about activated mechanisms of action. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor which triggersnon-genomic effects through c-Src. Considering that AhR/c-Srcaxispromotes breast cancer progression when is activated by ligand, this makes it a possible target to be induced by the acidic tumor microenvironment.Our aim was tostudythe effect of extracellular pH (pHe) 6.5 on AhR/c-Srcaxisand its correlation with cell migration and metalloproteases (MMP)-2 and 9 activities, using two breast cancer cell lines (MDA-MB-231and LM3) andthemammary epithelial cellsNMuMG. We found that acidosisinduces c-Src phosphorylationonly in breast cancer cellsthrough AhR, since it was preventedby the AhRinhibitor 4,7-o-phenanthroline (PHE). In addition, the pHe 6.5 increasesMDA-MB-231 and LM3 cell migrationas well asMMP-9 activity,and theseeffects were blocked with PHE or the c-Src inhibitor PP2.Cytosolic pH (pHi) was measured in cells treated with pHe 6.5, founding a reductionfrom 7.6 to 6.9. Amiloride is an inhibitor of the Na+/H+ exchange 1 protein, that it is known to reduce pHi. The MDA-MB-231 treatment with amilorideenhances c-Src phosphorylationin an AhR-dependent manner, suggesting thatthe reduction in pHi could be involved in AhR/c-Src activation.In conclusion, acidosis induces a pro-migratory phenotype in breast cancer cells through AhR/c-Srcsignaling.