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

MARIELA LENZE; MARÍA FLORENCIA CHERVO; MAURO EZEQUIEL CENCIARINI; SANTIAGO MADERA; MARA DE MARTINO; SOFIA BRUNI; FLORENCIA MERCOGLIANO; ROXANA SCHILLACI; ROSALIA INÉS CORDO RUSSO; CECILIA JAZMÍN PROIETTI; PATRICIA VIRGINIA ELIZALDE

Ciudad Autónoma de Buenos Aires

Congreso; Reunion Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica

Triple negative breast cancer (TNBC) encompasses tumors without clinically significant levels of estrogen/progesterone receptors and membrane ErbB-2 (MErbB-2) overexpression or gene amplification. TNBC tumors have poor prognosis and neither established biomarkers nor therapeutic targets. On the one hand, we and others have shown that MErbB-2 (tyrosine kinase receptor) migrates to the nucleus of BC cells (nuclear ErbB-2, NErbB-2) where it binds to promoters/enhancers of target genes to regulate BC proliferation and migration. Interestingly, we have previously shown that NErbB-2 is required for in vitro and in vivo TNBC growth. On the other hand, several reports have proposed the androgen receptor (AR), another member of the steroid receptor superfamily, as a new target in TNBC. AR is expressed in 10-53% of TNBC and was proved to be critical for BC proliferation. We and others have shown a functional interplay between growth factors and steroid hormone receptors signaling pathways in BC. We propose the existence of a cross-talk between AR and ErbB-2 signaling pathways which regulates the expression of genes involved in TNBC growth. The experimental model used was the human TNBC cell line MDA-MB-453 which displays high expression levels of AR and NErBb-2. By Western Blot, we evidenced that dihydrotestosterone (DHT) treatment for short times (minutes) induced tyrosine phosphorylation of ErBb-2 (at residues 877, 1221/1222 and 1248). By confocal microscopy, we observed that DHT also induced ErBb-2 and AR nuclear translocation and co-localization. Finally, both DHT and HRG (heregulin, one of the ErbBs´ ligands) up-regulated Erk5 protein levels, an ErBb-2 target gene that we have previously shown to be involved in BC proliferation. Our findings evidence that DHT-activated AR induces ErbB-2 rapid activation, nuclear translocation and co-localization, suggesting a functional cross-talk between both receptors which drives Erk5 regulation.