Estrogen exhibits a biphasic effect on prostate tumor growth through the estrogen receptor β-KLF5 pathway

Yuka Nakajima, Asami Osakabe, Tsuyoshi Waku, Takashi Suzuki, Kensuke Akaogi, Tetsuya Fujimura, Yukio Homma, Satoshi Inoue, Junn Yanagisawa

研究成果: Article査読

17 被引用数 (Scopus)

抄録

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17β-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor β (ERβ) or Krüppel-like zinc finger transcription factor 5 (KLF5). In addition, E2 suppressed KLF5-mediated transcription through ERβ, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERβ-KLF5 pathway and regulated prostate tumor growth without ERβ transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERβ and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

本文言語English
ページ(範囲)144-156
ページ数13
ジャーナルMolecular and cellular biology
36
1
DOI
出版ステータスPublished - 2016
外部発表はい

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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