Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway.
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). Ιn 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.
Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan nakajima@tara.tsukuba.ac.jp.
Yuka
Y
Nakajima
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Asami
A
Osakabe
Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Tsuyoshi
T
Waku
Department of Pathology and Histotechnology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Takashi
T
Suzuki
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Kensuke
K
Akaogi
Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Tetsuya
T
Fujimura
Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yukio
Y
Homma
Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Satoshi
S
Inoue
Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Junn
J
Yanagisawa
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D004958:Estradiol