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 vivoangiogenesis 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 pro-apoptoticFOXO1and pro-angiogenicPDGFAexpression. Furthermore, we revealed that a non-agonistic ER ligand GS-1405 inhibitedFOXO1andPDGFA expression through ERβ and 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.
Increased AKT Activity Contributes to Prostate Cancer Progression by Dramatically Accelerating Prostate Tumor Growth and Diminishing p27Kip1Expression
