Prostate cancer (PCa) is initially regulated by the androgen receptor (AR), a ligand-activated, transcription factor (hormone-sensitive PCa (HSPC)), but eventually become androgen-refractory or castration-resistant (CRPC) because of mechanisms that bypass the AR, including ErbB3, a member of the epidermal growth factor receptor (EGFR) family.
ErbB3 is synthesized in the cytoplasm and transported to the plasma membrane for ligand binding and dimerization, where it regulates downstream signaling, but nuclear forms are reported. Here, we demonstrate in prostatectomy samples that ErbB3 nuclear localization is observed in malignant, but not benign prostate. and that cytoplasmic (but not nuclear) ErbB3 correlated positively with AR expression but negatively with AR transcriptional activity. In support of the latter, androgen depletion upregulated cytoplasmic, but not nuclear ErbB3, while in vivo studies showed that castration suppressed ErbB3 nuclear localization in HSPC, but not CRPC tumors. In vitro treatment with the ErbB3 ligand heregulin-1β (HRG) induced ErbB3 nuclear localization, which was androgen-regulated in HSPC but not in CRPC. In turn, HRG upregulated AR transcriptional activity in CRPC but not in HSPC cells. Positive correlation between ErbB3 and AR expression was demonstrated in AR-null PC-3 cells where stable transfection of AR restored HRG-induced ErbB3 nuclear transport, while AR knockdown in LNCaP reduced cytoplasmic ErbB3. Mutations of ErbB3's kinase domain did not affect its localization but was responsible for cell viability in CRPC cells. Taken together, we conclude that AR expression regulated ErbB3 expression, its transcriptional activity suppressed ErbB3 nuclear translocation, and HRG binding to ErbB3 promoted it.
The Journal of biological chemistry. 2023 Jun 26 [Epub ahead of print]
Maitreyee K Jathal, Salma Siddiqui, Demitria M Vasilatis, Blythe P Durbin Johnson, Christiana Drake, Benjamin A Mooso, Leandro S D'Abronzo, Neelu Batra, Maria Mudryj, Paramita M Ghosh
Research Service, VA Northern California Health Care System, Mather, CA; Department of Medical Microbiology and Immunology, University of California Davis, CA., Research Service, VA Northern California Health Care System, Mather, CA., Research Service, VA Northern California Health Care System, Mather, CA; Department of Urologic Surgery, University of California Davis, Sacramento, CA., Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, CA., Department of Statistics, University of California Davis, Davis, CA., Department of Urologic Surgery, University of California Davis, Sacramento, CA., Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA., Research Service, VA Northern California Health Care System, Mather, CA; Department of Urologic Surgery, University of California Davis, Sacramento, CA; Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37380074