Androgen Receptor Highjacks ErbB-2 Nuclear Function to Induce Triple Negative Breast Cancer Growth

Abstract Triple negative breast cancer (TNBC) has poor prognosis and neither established biomarkers nor therapeutic targets. On the one hand androgen receptor (AR), a steroid hormone (SR) which is expressed in 10-53% of TNBC proved to be critical for BC proliferation, been proposed as new target TNBC. other hand, we others have shown that membrane ErbB-2 migrates nucleus (nuclear ErbB-2, NErbB-2) where it binds DNA at HER-2 associated sequences (HAS) regulate proliferation migration. Since previously functional interplay between growth factors SR signaling pathways BC, propose existence an interaction AR involved NErbB-2+/AR+ growth. The experimental model used was human cell line MDA-MB-453 displays high expression levels NErbB-2. By Western Blot (WB) found dihydrotestosterone (DHT) treatment short times (minutes) did not phosphorylation status residues Tyr1221/1222 1248 were constitutively activated. However, DHT led increase residue Tyr877 required nuclear latter effect blocked by antagonist enzalutamide (enza). Blockage Src activity with dasatinib inhibited DHT-induced Tyr877. Immunofluorescence confocal microscopy analyses subcellular fractionation studies demonstrated induced migration enza. chIP recruitment HAS site ERK5, gene FKBP5, classical responsive gene. WB transfection mutant unable translocate functions dominant inhibitor (hErbB-2ΔNLS), FKBP51 up-regulation DHT. Finally, microarray bioinformatics analysis identified 315 differentially genes (DEGs) presence NErbB-2 eviction. Enrichment showed DEGs belonged immune response interferon pathways. Kaplan-Meier revealed 6 significantly overall survival patients from METABRIC cohort: CXCL10, TAP1, STAT1, NMI, HLA-A NLRC5. Multivariate Cox regression combined independent predictor better clinical outcome (HR: 0.56, 95% CI 0.38-0.82, P = 0.003). In conclusion, our findings evidence DHT-activated induces Src-mediated rapid activation its sites DNA. Moreover, based on eviction signature favorable