CROSS-TALK BETWEEN ANDROGEN RECEPTOR AND ErbB-2 SIGNALING PATHWAYS IN TRIPLE-NEGATIVE BREAST CANCER

CENCIARINI MAURO; BRUNI SAFÍA; CORDO RUSSO ROSALÍA; CHERVO FLORENCIA; DE MARTINO MARA; SCHILLACI ROXANA; ELIZALDE PATRICIA; LENZE MARIELA; MADERA SANTIAGO; MERCOGLIANO FLORENCIA; PROIETTI ROSALÍA

Congreso; Reunión Conjunta de Sociedades de Biociencias- LXII Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Triple negative breast cancer (TNBC) encompassestumors withoutclinically significant levels of estrogen/progesteronereceptorsand membrane ErbB-2 (MErbB-2) overexpression or geneamplification.TNBC tumors have poor prognosis and neitherestablishedbiomarkers 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 itbinds to promoters/enhancers of target genes to regulate BC proliferationandmigration. Interestingly, we have previously shownthat NErbB-2 isrequired for in vitro and in vivo TNBC growth. On theother hand,several reports have proposed the androgen receptor(AR), anothermember of the steroid receptor superfamily, as a newtarget inTNBC. AR is expressed in 10-53% of TNBC and was provedto becritical for BC proliferation. We and others haveshown a functionalinterplay between growth factors and steroid hormonereceptorssignaling pathways in BC. We propose the existence ofa cross-talkbetween AR and ErbB-2 signaling pathways whichregulates the expressionof genes involved in TNBC growth. The experimentalmodelused was the human TNBC cell line MDA-MB-453 whichdisplayshigh expression levels of AR and NErBb-2. By WesternBlot, weevidenced that dihydrotestosterone (DHT) treatment forshort times(minutes) induced tyrosine phosphorylation of ErBb-2(at residues877, 1221/1222 and 1248). By confocal microscopy, weobservedthat DHT also induced ErBb-2 and AR nucleartranslocation andco-localization. Finally, both DHT and HRG (heregulin, one of theErbBs? ligands) up-regulated Erk5 protein levels, anErBb-2 targetgene that we have previously shown to be involved inBC proliferation.Our findings evidence that DHT-activated AR inducesErbB-2rapid activation, nuclear translocation andco-localization, suggestinga functional cross-talk between both receptors whichdrives Erk5regulation.