Epidermal growth factor enhances androgen receptor‑mediated bladder cancer progression and invasion via potentiation of AR transactivation

Hsieh,Teng-Fu; Chen,Chi-Cheng; Ma,Wen-Lung; Chuang,Wei-Min; Hung,Xiao-Fan; Tsai,Yi‑Ru; Lin,Meng-Hsueh   Amanda; Zhang,Qiaoxia; Zhang,Caixia; Chang,Chawnshang; Shyr,Chih-Rong

doi:10.3892/or.2013.2792

Epidermal growth factor enhances androgen receptor‑mediated bladder cancer progression and invasion via potentiation of AR transactivation

Authors:
- Teng-Fu Hsieh
- Chi-Cheng Chen
- Wen-Lung Ma
- Wei-Min Chuang
- Xiao-Fan Hung
- Yi‑Ru Tsai
- Meng-Hsueh Amanda Lin
- Qiaoxia Zhang
- Caixia Zhang
- Chawnshang Chang
- Chih-Rong Shyr
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Affiliations: Sex Hormone Research Center and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung 404, Taiwan, R.O.C., George Whipple Laboratory for Cancer Research, Departments of Pathology and Urology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
Published online on: October 10, 2013 https://doi.org/10.3892/or.2013.2792
Pages: 2917-2922

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Abstract

Androgen receptor (AR) plays a critical role in bladder cancer (BCa) development. Our early studies found AR knock-out mice (with few androgens and deleted AR) failed to develop BCa, yet 50% of castrated mice (with few androgens and existing AR) still developed BCa in an N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) carcinogen-induced BCa mouse model, suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens. The mechanism underlying this and/or which factors potentiate AR function at the castration level of androgen remains unclear. Epidermal growth factor (EGF), a key player in BCa progression, has been demonstrated to be able to potentiate AR transactivation in prostate cancer. In the present study, we found that EGF could increase BCa cell growth, migration and invasion in the presence of AR under the low amount of androgen and EGF was able to potentiate AR transactivation through EGFR by activating PI3K/AKT and MAPK pathway at castration androgen level. The increased suppression effects by EGFR inhibitor of PD168393 on AR function after addition of anti-androgen, Casodex, further suggested AR might play a key role in the effects of EGF on BCa progression and metastasis. Collectively, our results indicate that EGF may be able to potentiate AR transactivation that leads to enhancing BCa progression, which may help us to develop a better therapeutic approach to treat BCa via targeting both EGF and AR signaling.

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