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Sci. Signal., 12 April 2011
Vol. 4, Issue 168, p. ra22
[DOI: 10.1126/scisignal.2001551]

RESEARCH ARTICLES

Estrogen Regulates Tumor Growth Through a Nonclassical Pathway that Includes the Transcription Factors ERβ and KLF5

Yuka Nakajima1,2*, Kensuke Akaogi1*, Takashi Suzuki3, Asami Osakabe1, Chie Yamaguchi1, Nanae Sunahara1, Junji Ishida2, Koichiro Kako2, Sonoko Ogawa4, Tetsuya Fujimura5, Yukio Homma5, Akiyoshi Fukamizu2, Akiko Murayama1,2,6, Keiji Kimura1, Satoshi Inoue7,8,9, and Junn Yanagisawa1,2{dagger}

1 Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
2 Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
3 Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
4 Kansei, Behavioral and Brain Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
5 Department of Urology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
6 Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawasaki, Saitama 351-0198, Japan.
7 Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
8 Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
9 Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.

* These authors contributed equally to this work.

Abstract: Clinical evidence suggests that antiestrogens inhibit the development of androgen-insensitive prostate cancer. Here, we show that the estrogen receptor β (ERβ) mediates inhibition by the antiestrogen ICI 182,780 (ICI) and its enhancement by estrogen. ERβ associated with gene promoters through the tumor-suppressing transcription factor KLF5 (Krüppel-like zinc finger transcription factor 5). ICI treatment increased the recruitment of the transcription coactivator CBP [CREB (adenosine 3',5'-monophosphate response element–binding protein)–binding protein] to the promoter of FOXO1 through ERβ and KLF5, which enhanced the transcription of FOXO1. The increase in FOXO1 abundance led to anoikis in prostate cancer cells, thereby suppressing tumor growth. In contrast, estrogen induced the formation of complexes containing ERβ, KLF5, and the ubiquitin ligase WWP1 (WW domain containing E3 ubiquitin protein ligase 1), resulting in the ubiquitination and degradation of KLF5. The combined presence of KLF5 and ERβ positively correlated with longer cancer-specific survival in prostate cancer patients. Our results demonstrate that estrogens and antiestrogens affect prostate tumor growth through ERβ-mediated regulation of KLF5.

{dagger} To whom correspondence should be addressed. E-mail: junny{at}agbi.tsukuba.ac.jp

Citation: Y. Nakajima, K. Akaogi, T. Suzuki, A. Osakabe, C. Yamaguchi, N. Sunahara, J. Ishida, K. Kako, S. Ogawa, T. Fujimura, Y. Homma, A. Fukamizu, A. Murayama, K. Kimura, S. Inoue, J. Yanagisawa, Estrogen Regulates Tumor Growth Through a Nonclassical Pathway that Includes the Transcription Factors ERβ and KLF5. Sci. Signal. 4, ra22 (2011).

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