Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor...

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Estrogen receptor beta (ERβ) is expressed in prostate tissues, including epithelium, stroma, immune cells, and vasculature.
• ERβ inactivation in mice leads to epithelial hyperplasia and upregulation of androgen receptor (AR)-regulated genes, some associated with prostate cancer (PCa).
• ERβ is found in basal and luminal cells, while AR is primarily in luminal cells, highlighting distinct cellular roles and potential interactions.

Purpose of the Study:

• To investigate the mechanisms of ERβ action and its crosstalk with AR in prostate cancer.
• To analyze the transcriptomic effects of ERβ activation by estradiol and a synthetic ligand (LY3201) in engineered LNCaP PCa cells.

Main Methods:

• Utilized RNA sequencing (RNA-seq) to assess gene expression changes in AR-positive LNCaP cells engineered to express ERβ.
• Treated cells with estradiol or the synthetic ERβ ligand LY3201 to observe transcriptomic responses.
• Performed gene set analysis to identify enriched pathways and analyzed AR transcript, protein levels, and activity.

Main Results:

• ERβ activation by estradiol or LY3201 led to robust gene expression changes, with significant overlap and ligand-specific alterations.
• Down-regulated genes included key androgen-responsive genes (e.g., FKBP5, CAMKK2, TBC1D4).
• ERβ activation repressed AR transcript and protein levels, reduced AR transcriptional activity, and inhibited CAMKK2-target AMPK phosphorylation.

Conclusions:

• ERβ activation negatively regulates AR expression and activity in prostate cancer cells.
• These findings support a potential tumor-suppressive role for ERβ in prostate cancer (PCa).
• ERβ-mediated signaling pathways are implicated in controlling AR function within the prostate cancer context.