Abstract
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.
Highlights
The human prostate is an endocrine organ that depends on androgens to maintain its size and secretory function [50]
It has been shown that ERβ1 is clearly expressed in the nucleus of the epithelial cells in low-grade carcinomas while its expression is reduced in high-grade carcinomas [18,27]
The present results demonstrate that ERβ1 and ERβ2 isoforms are differentially regulated during cell cycle in the human prostate cancer cell line LNCaP and provide evidence that ERβ1 controls the G1 progression through non-genomic mechanisms
Summary
The human prostate is an endocrine organ that depends on androgens to maintain its size and secretory function [50]. Testosterone and 5-α-dihydrotestosterone are metabolized to 17β-estradiol by P450-aromatase [16] Both ERα and ERβ have been identified in the prostate, only the latter is expressed in the epithelial cells [18,42], where it has been suggested to bind natural estrogenic ligands. A decreased expression of ERβ mRNA and protein has been detected in breast, ovary and colon carcinomas [2,19,55], suggesting that ERβ might play a protective role in cancer development or progression It has been reported an increasing expression of ERβ2 with the transition from low-grade to high-grade prostate and breast carcinomas [17,20]. 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
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