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


Editor's Summary

Pro- and Antitumorigenic Ligands for Estrogen Receptor
Prostate cancer is a substantial cause of mortality among aging men. Growth of prostate tumors may initially be hormone-dependent and can thus be slowed by androgen ablation therapy; however, these cancers frequently become androgen-independent. Antiestrogens, such as ICI 182,780 (ICI), can block the development and progression of androgen-independent prostate cancers, whereas estrogens can promote growth of these cancers. Nakajima et al. investigated the mechanisms by which estrogens and antiestrogens exert their opposing effects on prostate tumor growth. They found that estrogen receptor β (ERβ) enhanced KLF5-mediated transcription of FOXO1, which encodes a protein that can promote cell death in prostate cancer cells. In contrast, estrogen elicited the association of an ubiquitin ligase with the KLF5-ERβ complex and promoted proteasomal degradation of KLF5. In mice injected with prostate cancer cells, ICI treatment decreased tumor size, whereas estrogen treatment promoted tumor growth. The presence of both ERβ and KLF5 in individuals with prostate tumors correlated with longer survival and histological profiles associated with less aggressive tumors. The accompanying Perspective by Leung and Ho discusses the biological and clinical implications of this research, including the intriguing possibility that estrogens may not be necessary for transcriptional activity of ERβ and thus may not be the primary ligand for ERβ in the prostate.

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).

Read the Full Text

KLF5 Activates MicroRNA 200 Transcription To Maintain Epithelial Characteristics and Prevent Induced Epithelial-Mesenchymal Transition in Epithelial Cells.
B. Zhang, Z. Zhang, S. Xia, C. Xing, X. Ci, X. Li, R. Zhao, S. Tian, G. Ma, Z. Zhu, et al. (2013)
Mol. Cell. Biol. 33, 4919-4935
   Abstract »    Full Text »    PDF »
Insight into the mechanisms of action of estrogen receptor {beta} in the breast, prostate, colon, and CNS.
P. Dey, R. P. A. Barros, M. Warner, A. Strom, and J.-A. Gustafsson (2013)
J. Mol. Endocrinol. 51, T61-T74
   Abstract »    Full Text »    PDF »
High circulating estrogens and selective expression of ER{beta} in prostate tumors of Americans: implications for racial disparity of prostate cancer.
Z. Y. Abd Elmageed, K. Moroz, S. K. Srivastav, Z. Fang, B. E. Crawford, K. Moparty, R. Thomas, and A. B. Abdel-Mageed (2013)
Carcinogenesis 34, 2017-2023
   Abstract »    Full Text »    PDF »
The Glucocorticoid Receptor and KLF15 Regulate Gene Expression Dynamics and Integrate Signals through Feed-Forward Circuitry.
S. K. Sasse, C. M. Mailloux, A. J. Barczak, Q. Wang, M. O. Altonsy, M. K. Jain, S. M. Haldar, and A. N. Gerber (2013)
Mol. Cell. Biol. 33, 2104-2115
   Abstract »    Full Text »    PDF »
Kruppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens.
K. Takagi, Y. Miki, Y. Onodera, Y. Nakamura, T. Ishida, M. Watanabe, S. Inoue, H. Sasano, and T. Suzuki (2012)
Endocr. Relat. Cancer 19, 741-750
   Abstract »    Full Text »    PDF »
Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation.
S. M. Haldar, D. Jeyaraj, P. Anand, H. Zhu, Y. Lu, D. A. Prosdocimo, B. Eapen, D. Kawanami, M. Okutsu, L. Brotto, et al. (2012)
PNAS 109, 6739-6744
   Abstract »    Full Text »    PDF »
Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation.
X. Sun, L. Zhang, H. Xie, H. Wan, B. Magella, J. A. Whitsett, and S. K. Dey (2012)
PNAS 109, 1145-1150
   Abstract »    Full Text »    PDF »
Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer.
B. Sahu, M. Laakso, K. Ovaska, T. Mirtti, J. Lundin, A. Rannikko, A. Sankila, J.-P. Turunen, M. Lundin, J. Konsti, et al. (2011)
EMBO J. 30, 3962-3976
   Abstract »    Full Text »    PDF »
Estrogen Receptor {beta}: Switching to a New Partner and Escaping from Estrogen.
Y.-K. Leung and S.-M. Ho (2011)
Science Signaling 4, pe19
   Abstract »    Full Text »    PDF »

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