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

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