PMID:21487105

Citation	Nakajima, Y, Akaogi, K, Suzuki, T, Osakabe, A, Yamaguchi, C, Sunahara, N, Ishida, J, Kako, K, Ogawa, S, Fujimura, T, Homma, Y, Fukamizu, A, Murayama, A, Kimura, K, Inoue, S and Yanagisawa, J (2011) Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERβ and KLF5. Sci Signal 4:ra22
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.
Links	PubMed Online version:10.1126/scisignal.2001551
Keywords	Aged; Animals; Antineoplastic Agents, Hormonal/pharmacology; CREB-Binding Protein/genetics; CREB-Binding Protein/metabolism; Cell Line, Tumor; Cell Proliferation/drug effects; Estradiol/analogs & derivatives; Estradiol/pharmacology; Estrogen Receptor beta/genetics; Estrogen Receptor beta/metabolism; Estrogens/pharmacology; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Humans; Immunoblotting; Kruppel-Like Transcription Factors/genetics; Kruppel-Like Transcription Factors/metabolism; Male; Mice; Middle Aged; Promoter Regions, Genetic/genetics; Prostatic Neoplasms/drug therapy; Prostatic Neoplasms/metabolism; Prostatic Neoplasms/pathology; Protein Binding/drug effects; RNA Interference; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/drug effects; Tumor Burden/drug effects; Xenograft Model Antitumor Assays
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