Agustina Roldán Deamicis¹, Robert H. Oakley², Sergio Andonegui Helguera³, Mariela B. Lenze¹, Santiago Madera¹, Rosalia I. Cordo Russo¹, María F. Chervo¹, Roxana Schillaci¹, Cristóbal Fresno³, John A. Cidlowski², Patricia V. Elizalde¹, Cecilia J. Proietti¹
We propose the existence of an interaction between androgen receptor (AR) and ErbB-2 which is involved in NErbB-2+/AR+ BC 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 found that dihydrotestosterone (DHT) treatment for short periods of time (minutes) led to an increase in ErbB-2 phosphorylation at Tyr877 which we have proved to be required for ErbB-2 nuclear migration. By Immunofluorescence and subcellular fractionation studies we demonstrated that DHT induced ErbB-2 nuclear migration. By chIP we found that DHT induced ErbB-2 recruitment to a HAS site in FKBP5, a classical AR responsive gene. Finally, by microarray we identified 315 differentially expressed genes in the presence of DHT and NErbB-2 eviction by transfection with an ErbB-2 mutant which is unable to translocate to the nucleus and functions as a dominant negative inhibitor of ErbB-2 nuclear migration (hErbB-2ΔNLS). Multivariate Cox regression analysis identified the combined expression of 6 genes (CXCL10, TAP1, STAT1, NMI, HLA-A and NLRC5) as an independent predictor of better clinical outcome in TNBC. In conclusion, our findings evidenced that DHT-activated AR induces ErbB-2 rapid activation and its migration to the nucleus where it binds to HAS sites in the DNA. Moreover, based on the diffetentially expressed genes of NErbB-2 eviction in presence of DHT we identified a gene signature associated with favorable outcome in TNBC.