Estrogen Receptor β: Switching to a New Partner and Escaping from Estrogen

Yuet-Kin Leung^1,2,3 and Shuk-Mei Ho^1,2,3*

¹ Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati Medical Center, Kettering Complex, Room 128, 3223 Eden Avenue, P.O. Box 670056, Cincinnati, OH 45267, USA.
² Center of Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
³ Cincinnati Cancer Center, College of Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.

Abstract: Estrogen receptor (ER) β, the "second" ER, plays a gatekeeper role by inhibiting cell proliferation, promoting apoptosis, and impeding the progression of prostate cancer. Ironically, its presumed ligand, 17β-estradiol, promotes cancer development in experimental models. The mechanisms underlying the interplay between estrogens and ERβ in prostate cancer remain largely unclear. Research on a previously unknown tethering partner of ERβ, Krüppel-like zinc finger transcription factor 5 (KLF5), and its downstream gene target (FOXO1) helps to unlock this puzzle. 17β-Estradiol is not required to maintain the tumor-suppressive function of ERβ in the prostate, a tissue with limited estrogen availability; moreover, the presence of 17β-estradiol abrogates ERβ- and KLF5-mediated signaling and promotes cellular proliferation. Future research into ERβ will likely involve this estrogen independency and the preference for binding nonclassical DNA elements through tethering. The development of ERβ-based therapies may lead to improved drug efficacy.

* Corresponding author. E-mail, shuk-mei.ho{at}uc.edu

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