Estrogen receptor beta displays cell cycle-dependent expression and regulates the G1 phase through a non-genomic mechanism in prostate carcinoma cells.

Background: It is well known that estrogens regulate cell cycle progression, but the specific contributions and mechanisms of action of the estrogen receptor beta (ER beta) remain elusive. Methods: We have analyzed the levels of ER beta 1 and ER beta 2 throughout the cell cycle, as well as the mechanisms of action and the consequences of the over-expression of ER beta 1 in the human prostate cancer LNCaP cell line. Results: Both ER beta 1 mRNA and protein expression increased from the G1 to the S phase and decreased before entering the G2/M phase, whereas ER beta 2 levels decreased during the S phase and increased in the G2/M phase. ER beta 1 protein was detected in both the nuclear and non-nuclear fractions, and ER beta 2 was found exclusively in the nucleus. Regarding the mechanisms of action, endogenous ER beta was able to activate transcription via ERE during the S phase in a ligand-dependent manner, whereas no changes in AP1 and NFkB transactivation were observed after exposure to estradiol or the specific inhibitor ICI 182,780. Over-expression of either wild type ER beta 1 or ER beta 1 mutated in the DNA-binding domain caused an arrest in early G1. This arrest was accompanied by the interaction of over-expressed ER beta 1 with c-Jun N-terminal protein kinase 1 (JNK1) and a decrease in c-Jun phosphorylation and cyclin D1 expression. The administration of ICI impeded the JNK1 -ER beta 1 interaction, increased c-Jun phosphorylation and cyclin D1 expression and allowed the cells to progress to late G1, where they became arrested. Conclusions: Our results demonstrate that, in LNCaP prostate cancer cells, both ER beta isoforms are differentially expressed during the cell cycle and that ER beta regulates the G1 phase by a non-genomic mechanism.