CELL MIGRATION INDUCED BY HEREGULIN INVOLVES TGFΒ SIGNALING ACTIVATION IN LUMINAL BREAST CANCER CELLS

ANGELA LARA MONTERO; MERCEDES MONTANI ; AGUSTIN GONALEZ; JULIETA AISEMBERG; WERTHEIMER EVA; DE LAURENTIIS ANDREA; OMAR A. COSO; EDITH C. KORDON

Mar del Plata

Congreso; Reunión Anual SAIC 2023; 2023

SAIC

Previous results indicated that in luminal breast cancer(BC) cells, Heregulin (HRG) increased cell migrationby ErbB3/P-Rex/Rac1 signaling activation and that thispathway also induced TGFβ2 expression. Therefore,our goal was to determine whether the TGFβ signalingpathway was involved in Hrg-induced BC cell migration.To that end, we performed experiments using specificpharmacological inhibitors and transient gene silencingfor blocking mediators of the involved pathways. Analysisof mRNA (by RT-qPCR) and protein (Western Blotand immunofluorescence) levels as well as wound-healingassays in luminal BC cells, T47D and MCF-7, wereperformed. Our results show that Hrg induces not onlyTGFβ2, but also TGFβ1, TGFBR1, TGFBR2, SMAD3,and SMAD4 expression, all members of the canonicalTGFβ signaling pathway. Supporting these data, wefound positive correlations between HRG and TGFβ1,TGFβ2, TGFβ3, and TGFBR3 protein content in proteomicdata sets from breast cancer samples. In addition,HRG treatment induced phosphorylation and nucleartranslocation of SMAD-3, but this activation was blockedby adding SB525334 a TGFBR1 inhibitor. Furthermore,this treatment also inhibited HRG-induced cell migration.On the other hand, upon HRG treatment, Smad3phosphorylation was not affected by P-REX1 silencingand Rac1 activation increases when TGFBR1 is inhibited.Taken together, our results indicate that HRG inducescell migration of luminal breast cancer cells not onlyby activating the ErbB3/P-Rex/Rac1 signaling, but alsoby inducing TGFβ ligands and SMAD-dependent pathways.However, the two signaling cascades seem not tosynergize, but to compete with each other. In summary,we propose that our findings may contribute to the questfor new combination therapies that may help to developmore successful treatments for luminal breast cancer.