title: Epidermal growth factor induces bladder cancer cell proliferation through             activation of the androgen receptor.
abstract: Androgen receptor (AR) signals have been suggested to contribute to bladder             tumorigenesis and cancer progression. Activation of epidermal growth factor receptor             (EGFR) also leads to stimulation of bladder tumor growth. However, crosstalk between             AR and EGFR pathways in bladder cancer remains uncharacterized. We have recently             shown that androgens activate the EGFR pathway in bladder cancer cells. The purpose             of this study was to investigate the effects of EGF on AR activity in bladder             cancer. EGF increased AR transcriptional activity by 1.2-, 1.9- and 2.0-fold in             UMUC3, 5637-AR and J82-AR cell lines, respectively, over mock treatment and a             specific EGFR inhibitor, PD168393, antagonized the EGF effect. Combined treatment             of EGF and dihydrotestosterone (DHT) further induced AR transactivation while             an AR antagonist, hydroxyflutamide (HF), abolished the effect of not only DHT             but also EGF. In growth assays, EGF alone/DHT alone/EGF+DHT increased cell numbers             by 16/12/19%, 6/14/18% and 30/12/38% in UMUC3-control-shRNA, 5637-AR and J82-AR,             respectively, whereas the effects of EGF were marginal or less significant in             UMUC3-AR-shRNA (8%) or AR-negative 5637-V (<1%) and J82-V (17%) cells. HF treatment             at least partially counteracted the EGF effect on the growth of AR-positive cells.             Western blotting demonstrated that EGF, especially in the presence of DHT, upregulated             the expression of the p160 coactivator TIF2 and HF again blocked this stimulation.             Co-immunoprecipitation revealed the association between AR and estrogen receptor             (ER)-β or Src in UMUC3 cells and stronger associations with EGF treatment, implying             the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and             cell growth. Current results, thus, suggest that EGF promotes bladder cancer cell             proliferation via modulation of AR signals. Taken together with our previous findings,             crosstalk between EGFR and AR pathways can play an important role in the progression             of bladder cancer.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of                     Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Izumi
authors.forename: Yichun
authors.initials: Y
authors.lastname: Zheng
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Zaengle
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019061:src-Family Kinases