Cross-talk between androgen receptor and ErbB-2 signaling pathways in triple-negative breast cancer

LENZE M; CHERVO MF; CENCIARINI M; MADERA S; DE MARTINO M; BRUNI S; MERCOGLIANO MF; SCHILLACI R; CORDO RUSSO RI; PROIETTI CJ; ELIZALDE PV

Buenos Aires

Congreso; LXII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2017

Sociedad Argentina de Investigaciones Clinicas

Triple negative breast cancer (TNBC) encompasses tumors withoutclinically significant levels of estrogen/progesterone receptorsand membrane ErbB-2 (MErbB-2) overexpression or gene amplification.TNBC tumors have poor prognosis and neither establishedbiomarkers nor therapeutic targets. On the one hand, we and othershave shown that MErbB-2 (tyrosine kinase receptor) migrates to thenucleus of BC cells (nuclear ErbB-2, NErbB-2) where it binds to promoters/enhancers of target genes to regulate BC proliferation andmigration. Interestingly, we have previously shown that NErbB-2 isrequired for in vitro and in vivo TNBC growth. On the other hand,several reports have proposed the androgen receptor (AR), anothermember of the steroid receptor superfamily, as a new target inTNBC. AR is expressed in 10-53% of TNBC and was proved to becritical for BC proliferation. We and others have shown a functionalinterplay between growth factors and steroid hormone receptorssignaling pathways in BC. We propose the existence of a cross-talkbetween AR and ErbB-2 signaling pathways which regulates the expressionof genes involved in TNBC growth. The experimental modelused was the human TNBC cell line MDA-MB-453 which displayshigh expression levels of AR and NErBb-2. By Western Blot, weevidenced that dihydrotestosterone (DHT) treatment for short times(minutes) induced tyrosine phosphorylation of ErBb-2 (at residues877, 1221/1222 and 1248). By confocal microscopy, we observedthat DHT also induced ErBb-2 and AR nuclear translocation andco-localization. Finally, both DHT and HRG (heregulin, one of theErbBs? ligands) up-regulated Erk5 protein levels, an ErBb-2 targetgene that we have previously shown to be involved in BC proliferation.Our findings evidence that DHT-activated AR induces ErbB-2rapid activation, nuclear translocation and co-localization, suggestinga functional cross-talk between both receptors which drives Erk5regulation.