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

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

Buenos Aires

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

Edith Kordon, Claudia Lanari

Acidosis is animportant factor on tumor development, but little is known about activated mechanismsof action. The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor whichtriggers non-genomic effects through c-Src. Considering that AhR/c-Src axis promotesbreast cancer progression when is activated by ligand, this makes it a possibletarget to be induced by the acidic tumor microenvironment. Our aim was to studythe effect of extracellular pH (pHe) 6.5 on AhR/c-Src axis and its correlationwith cell migration and metalloproteases (MMP)-2 and 9 activities, using twobreast cancer cell lines (MDA-MB-231 and LM3) and the mammary epithelial cells NMuMG.We found that acidosis induces c-Src phosphorylation only in breast cancercells through AhR, since it was prevented by the AhR inhibitor 4,7-o-phenanthroline(PHE). In addition, the pHe 6.5 increases MDA-MB-231 and LM3 cell migration aswell as MMP-9 activity, and these effects were blocked with PHE or the c-Srcinhibitor PP2. Cytosolic pH (pHi) was measured in cells treated with pHe 6.5, foundinga reduction from 7.6 to 6.9. Amiloride is an inhibitor of the Na+/H+ exchange 1protein, that it is known to reduce pHi. The MDA-MB-231 treatment with amilorideenhances c-Src phosphorylation in an AhR-dependent manner, suggesting that thereduction 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.<!-- /* 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;}.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;}