Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
International Journal of Oncology (Impact Factor: 2.77). 08/2012; 41(5):1587-92. DOI: 10.3892/ijo.2012.1593
Source: PubMed

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.

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    ABSTRACT: Although accumulating preclinical evidence indicates the involvement of androgen receptor signals in bladder cancer (BC) development, its clinical relevance remains unclear. We aimed to evaluate the predictive role of androgen deprivation therapy (ADT) in BC recurrence in prostate cancer (PC) patients. We retrospectively reviewed 20,328 patients with PC diagnosed during 1991–2013 and identified 239 (1.2%) men having primary BC. After excluding ineligible patients, 162 patients made up a final cohort. With a median follow-up of 62 months, 38 (50%) of 76 control patients without ADT experienced BC recurrence, while 19 (22%) of 86 did in ADT group. Thus, patients having received ADT for their PC showed a significantly lower risk of BC recurrence (5-year actuarial recurrence-free survival: 76% v 40%; P < 0.001) and also had a significantly smaller number of recurrence episodes (5-year cumulative recurrence: 0.44 v 1.54; P < 0.001), compared to the control patients. A multivariable analysis revealed ADT as an independent prognosticator (hazard ratio, 0.29; 95% confidence interval, 0.17–0.49) for BC recurrence. This is the first clinical study showing that ADT significantly reduces the risk of BC recurrence.
    Oncotarget 12/2014; 5(24). · 6.63 Impact Factor
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    Revista de sanidad militar 09/2014;
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    ABSTRACT: Recent evidence suggests the involvement of sex hormone receptors in bladder cancer initiation, while precise functions of androgens and estrogens in the carcinogenesis step remain poorly understood. We recently found down-regulation of GATA3, a zinc-finger transcription factor and a new urothelial marker, in bladder cancer, which also correlated with expression status of androgen receptor (AR) and estrogen receptors (ERs). We here assessed whether GATA3 acted as a suppressor of bladder tumorigenesis and sex hormones exerted an influence on GATA3 in non-neoplastic urothelial cells. Androgen (R1881, dihydrotestosterone) treatment in SVHUC immortalized normal urothelial cells stably expressing AR (SVHUC-AR) decreased GATA3 expression at both mRNA and protein levels, which was abolished by anti-androgens. Conversely, 17β-estradiol treatment increased it in SVHUC-control endogenously expressing ERβ. GATA3 levels were also found to be higher in intact female mouse bladders compared with intact males, and orchiectomy/ovariectomy augmented/reduced GATA3 expression, respectively, which was at least partially restored by dihydrotestosterone/17β-estradiol supplement. Additionally, GATA3 silencing via short hairpin RNA (shRNA) promoted cell proliferation of SVHUC with exposure to a chemical carcinogen 3-methylcholanthrene. In vitro transformation assay with 3-methylcholanthrene then showed a significantly higher number of colonies in SVHUC-AR/GATA3-shRNA, compared with control SVHUC, and R1881 further induced colony formation. GATA3 knockdown also resulted in down-regulation of the molecules that play a protective role in bladder tumorigenesis (i.e. UGT1A, PTEN, p53, p21) and up-regulation of oncogenic genes (i.e. c-myc, cyclin D1, cyclin D3, cyclin E, FGFR3). Thus, GATA3 likely prevented neoplastic transformation of urothelial cells. Furthermore, sex hormone signals contrary regulated GATA3 in the bladder. These findings may offer not only a molecular basis for the gender-specific difference in bladder cancer incidence but also great potential for androgen deprivation as a chemopreventive option for tumor recurrence.

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