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

• Published in: British journal of clinical pharmacology Vol. 85; no. 9; pp. 2143 - 2154
• Main Authors: Rivero, Ezequiel Mariano, Martinez, Leandro Marcelo, Bruque, Carlos David, Gargiulo, Lucia, Bruzzone, Ariana, Lüthy, Isabel Alicia
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01-09-2019
• Subjects: adrenoceptors; Biomarkers, Tumor - analysis; Biomarkers, Tumor - metabolism; Breast - pathology; breast cancer patients; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Datasets as Topic; Disease-Free Survival; Female; Follow-Up Studies; Gene Expression Profiling; Humans; Middle Aged; Neoplasm Recurrence, Local; Oligonucleotide Array Sequence Analysis; Original; Prognosis; prognostic factors; Receptors, Adrenergic, alpha-2 - analysis; Receptors, Adrenergic, alpha-2 - metabolism; Receptors, Adrenergic, beta-2 - analysis; Receptors, Adrenergic, beta-2 - metabolism; breast cancer patients; prognostic factors; adrenoceptors
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.14030

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.