Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

Abstract

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.

ACKNOWLEDGMENTS

We sincerely thank A. Fukamizu for a critical reading of the manuscript and helpful scientific input. We are also grateful to N. Ohnuma for valuable discussions and technical advice.

This work was supported by a Grant-in Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (23790075 to Y.N.), the research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan (to J.Y.), and the Open Innovation Core (OIC) project (Yuka Nakajima; a member of OIC) of Life Science Center, Tsukuba Advance Research Alliance (TARA), University of Tsukuba, Japan.

Additional information

Funding

The Open Innovation Core (OIC) project of Life Science Center, Tsukuba Advance Research Alliance (TARA), University of Tsukuba, Japan, provides the research facility for Yuka Nakajima.