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FGFR1 abrogates inhibitory effect of androgen receptor concurrent with induction of androgen‐receptor variants in androgen receptor‐negative prostate tumor epithelial cells
Author(s) -
Kobayashi Masashi,
Huang Yanqing,
Jin Chengliu,
Luo Yongde,
Okamoto Tetsuji,
Wang Fen,
McKeehan Wallace L.
Publication year - 2011
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21386
Subject(s) - androgen receptor , ectopic expression , androgen , biology , population , cancer research , endocrinology , medicine , prostate cancer , cell growth , cell culture , cancer , hormone , genetics , environmental health
BACKGROUND Despite dramatic positive effects, there is evidence that the androgen receptor (AR) may negatively influence prostate tumor progression. Understanding the AR repressor function and how it is subverted is of particular importance in anti‐androgen and AR intervention strategies. METHODS AR, resident FGFR2IIIb, and ectopic FGFR1 were expressed by transfection in the AR‐negative epithelial cell line DTE that predominates in cell culture of AR‐positive androgen‐responsive model Dunning R3327 rat prostate tumors. Androgen‐responsiveness at transcription was measured by a luciferase reporter. Cell population growth rates were assessed by cell counts, DNA synthesis, and expression of cell cycle genes. AR variants (ARVs) were assessed by immunochemistry and nuclease protection of mRNA. RESULTS Expression of AR inhibited cell population growth of AR‐negative DTE cells at the G1–S phase of the cell cycle. Ectopic FGFR1, but not resident FGFR2IIIb abrogated the growth inhibitory effects of AR. Appearance of ARVs was coincident with co‐expression of FGFR1 and AR and abrogation of the AR‐dependent inhibition of cell growth. CONCLUSIONS DTE cells may represent non‐malignant AR‐negative progenitors whose population is restricted by activation of AR in vivo. Ectopic expression of epithelial FGFR1, a common observation in tumors, overrides the inhibition of AR and thus may contribute to evolution of androgen and AR independent tumors. These results are consistent with the notion that some tumor cells are negatively restricted by AR and are unleased by androgen‐deprivation or ectopic expression of FGFR1. ARV's may play a role in the bypass of the negative restrictions of AR. Prostate 71:1691–1700, 2011. © 2011 Wiley‐Liss, Inc.