Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study

Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays was used to characterise a1b, a2c and b22 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong a1b expression occurred in large high grade (P\0.0001), HER2? (P\0.0001) or basal-like (CK5/6, P = 0.0005; CK14, P = 0.0001; EGFR, P = 0.003) cancers, showing increased proliferation (Mib1, P = 0.002), decreased apoptosis (Bcl2, P\0.0001) and poor NPI membership (P = 0.001). a1b expression correlated with poor cancer-specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong a2c was over-expressed in high grade (P = 0.007), HER3? (P = 0.002) and HER4? (P\ 0.0001) cancers with borderline increase in EGFR, p53 and MIB1 proteins, and inverse association with hormonal (PgR, P = 0.002) phenotype. In contrast, strong b2 expression occurred in small-size, luminal-like (ER?, P\0.001) tumours of low grade (P\0.001) and lymph node stage (P = 0.027) that showed poor prognosis when hormonal treatment was withheld. Adrenoceptors were not found to be independent predictors of clinical outcome. Alpha1b and a2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong b2 adrenoceptor expression is seen in patients with a luminal (ER?) tumour phenotype and good prognosis, due to benefits derived from hormonal therapy. These findings suggest a possible role for targeted therapy using adrenoceptor antagonists.