Prognostic significance of α‐ and β2‐adrenoceptor gene expression in breast cancer patients

Abstract

Aims Breast cancer is the most frequently diagnosed and leading cause of cancer death among women worldwide. It was classified within molecular intrinsic subtypes: luminal A, luminal B, human epidermal growth factor receptor 2‐enriched and basal‐like. Epinephrine and norepinephrine, released during stress, bind to adrenoceptors. α2‐adrenoceptors are encoded by the ADRA2A, ADRA2B and ADRA2C genes and β2 by ADRB2. Methods We compiled several publicly available Affymetrix gene expression datasets, obtaining a large cohort of 1924 patients with distant metastasis‐free survival (DMFS) data and evaluated the association between adrenoceptor expression, clinicopathological markers and outcome. Results ADRA2A high expressing tumours also expressed hormone receptors and presented diminished tumour size, grade and not compromised lymph nodes. ADRB2 high expression was found in smaller, low grade, oestrogen receptor‐positive tumours. Both were significantly associated with the absence of metastasis. High expression of ADRA2C was positively associated with increased tumour size and metastatic relapse. We observed a significant increase in DMFS of patients with high ADRA2A (hazard ratio 0.54, 95% CI 0.45–0.65, P < .001) and ADRB2 (0.77, 0.64–0.93, P = .006) expression and a decrease with ADRA2C high expression (1.45, 1.16–1.81, P = .001). For patients with luminal tumours, ADRA2A was the only factor that retained its significance as an independent predictor of DMFS while ADRA2C expression was an independent predictor for worse prognosis in basal‐like tumours. Conclusions We herein provide new insight for a potential role of ADRA2A and ADRA2C in breast cancer. In low‐ and medium‐income countries, their incorporation to routine immunohistochemistry analysis of biopsies or tumour samples, could provide additional low‐cost prognostic factors.

Prognostic and Predictive Impact of Beta-2 Adrenergic Receptor Expression in HER2-Positive Breast Cancer

“…Rivero et al 42 evaluated the correlation between ADRB2 expression and distant-metastasis-free survival in 1924 patients with early breast cancer, demonstrating that a high expression of ADBR2 was significantly correlated with a favorable prognosis in the overall study population (P ¼ .006). Notably, no significant association between ADRB2 expression and prognosis was observed in the HER2þ subgroup (P ¼ .412); however, the limited number of HER2þ patients included (n ¼ 50) precludes definitive conclusions.…”

“…Interestingly, ADRB2 expression was correlated with genes involved in T-cell activation and inflammatory response in this study, corroborating our findings. 42 Potential limitations have to be considered when interpreting our results. Data were extracted from publicly available datasets and not collected prospectively.…”

Identification of Key lncRNA–mRNA Pairs and Functional lncRNAs in Breast Cancer by Integrative Analysis of TCGA Data

“…Meanwhile, two candidate genes (ADRA2A and DTL) obtained by comparison screening have been reported in cancer. In breast cancer, for patients with luminal tumors, ADRA2A was an independent predictor of DMFS and the only factor that preserves its importance ( Rivero et al, 2019 ). DTL depletion resulted in the disruption of the mitotic proteins cyclin B, Cdt2, CDK1, and aurora as well as the upregulation of the cell cycle arrest gene p21 ( Ishii et al, 2010 ; Slenn et al, 2014 ).…”

Identification of a Metabolism-Related Risk Signature Associated With Clinical Prognosis in Glioblastoma Using Integrated Bioinformatic Analysis

“…KLF15 has been reported to inhibit cell growth in lung adenocarcinoma (37), gastric cancer (38), and colorectal cancer (39), and can be used to predict prognosis. High ADRA2A expression was associated with poor overall survival for breast (40) and bladder cancer (41). As a genetic marker, RNASEL has been linked to lethal prostate cancer (42).…”