Down-regulation of ADRB2 expression is associated with small cell neuroendocrine prostate cancer and adverse clinical outcomes in castration-resistant prostate cancer.
OBJECTIVES: The net oncogenic effect of β2-adrenergic receptor ADRB2, whose downstream elements induce neuroendocrine differentiation and whose expression is regulated by EZH2, is unclear. ADRB2 expression and associated clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) are unknown. METHODS AND MATERIALS: This was a retrospective analysis of a multi-center, prospectively enrolled cohort of mCRPC patients. Metastatic biopsies were obtained at progression, and specimens underwent laser capture microdissection and RNA-seq. ADRB2 expression was stratified by histology and clustering based on unsupervised hierarchical transcriptome analysis and correlated with EZH2 expression; an external dataset was used for validation. The association between ADRB2 expression and overall survival (OS) was assessed by log-rank test and a multivariable Cox proportional hazard model. RESULTS: One hundred and twenty-seven patients with progressive mCRPC had sufficient metastatic tumor for RNA-seq. ADRB2 expression was lowest in the small cell-enriched transcriptional cluster (P < 0.01) and correlated inversely with EZH2 expression (r = -0.28, P < 0.01). These findings were validated in an external cohort enriched for neuroendocrine differentiation. Patients with tumors harboring low ADRB2 expression (lowest quartile) had a shorter median OS than those with higher (9.5 vs. 20.5 months, P = 0.02). In multivariable analysis, low ADRB2 expression was associated with a trend toward shorter OS (HR for death = 1.54, 95%CI 0.98-2.44). Conversely, higher expression of upstream transcriptional regulator EZH2 was associated with shortened OS (HR for death = 3.01, 95%CI 1.12-8.09). CONCLUSIONS: Low ADRB2 expression is associated with neuroendocrine differentiation and is associated with shortened survival. EZH2 is a potential therapeutic target for preventing neuroendocrine transdifferentiation and improving outcomes in mCRPC. Further studies of agents targeting β-adrenergic signaling are warranted.
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Related Subject Headings
- Urology & Nephrology
- Survival Rate
- Retrospective Studies
- Receptors, Adrenergic, beta-2
- Prostatic Neoplasms, Castration-Resistant
- Middle Aged
- Male
- Humans
- Gene Expression Regulation, Neoplastic
- Down-Regulation
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Urology & Nephrology
- Survival Rate
- Retrospective Studies
- Receptors, Adrenergic, beta-2
- Prostatic Neoplasms, Castration-Resistant
- Middle Aged
- Male
- Humans
- Gene Expression Regulation, Neoplastic
- Down-Regulation