estrogen receptor beta displays cell cycle dependent expression and regulates the g1 phase through a non genomic mechanism in prostate carcinoma cells

• DOI: 10.3233/clo-2008-0430
• Publication Date: 2008-01-01
• Authors: Jordi Barquinero; Jordi Petriz; Albert Santamaria...; Joaquim Bellmunt; Francina Munell; Jaume Reventós; Tomàs Pinós; Anna Barbosa-Deso...; Sandra López-Avilés; Antoni Hurtado; Inés de Torres; Joan Morote
• Keywords: Male; Transcriptional Activation; 0301 basic medicine; Cell Line; S Phase; 03 medical and health sciences; Estrogen Receptor beta; Humans; Transgenes; Fulvestrant; RC254-282; Binding Sites; QH573-671; Estradiol; Gene Expression Profiling; Estrogen Antagonists; G1 Phase; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Prostatic Neoplasms; 3. Good health; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Mutagenesis, Site-Directed; Mutant Proteins; Other; Cytology; Protein Binding

Background: It is well known that estrogens regulate cell cycle progression, but the specific contributions and mechanisms of action of the estrogen receptor beta (ERβ) remain elusive.Methods: We have analyzed the levels of ERβ1 and ERβ2 throughout the cell cycle, as well as the mechanisms of action and the consequences of the over-expression of ERβ1 in the human prostate cancer LNCaP cell line.Results: Both ERβ1 mRNA and protein expression increased from the G1 to the S phase and decreased before entering the G2/M phase, whereas ERβ2 levels decreased during the S phase and increased in the G2/M phase. ERβ1 protein was detected in both the nuclear and non-nuclear fractions, and ERβ2 was found exclusively in the nucleus. Regarding the mechanisms of action, endogenous ERβ was able to activate transcription via ERE during the S phase in a ligand-dependent manner, whereas no changes in AP1 and NFκB transactivation were observed after exposure to estradiol or the specific inhibitor ICI 182,780. Over-expression of either wild type ERβ1 or ERβ1 mutated in the DNA-binding domain caused an arrest in early G1. This arrest was accompanied by the interaction of over-expressed ERβ1 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–ERβ1 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 ERβ isoforms are differentially expressed during the cell cycle and that ERβ regulates the G1 phase by a non-genomic mechanism.