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

Abstract

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 α1b, α2c and β(2)2 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong α1b 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). α1b expression correlated with poor cancer-specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong α2c 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 β(2) 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 α2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong β(2) 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.

Adrenergic signaling promotes angiogenesis through endothelial cell-tumor cell crosstalk

“…The results of these studies indicate the important roles of the Notch ligands and Notch signaling pathway in breast cancer (Stylianou et al 2006). Results from previous studies including ours have indicated that b2-AR is overexpressed in breast cancer tissues and certain types of breast cancer cell lines (Powe et al 2011, Shi et al 2011. Catecholamine-induced activation of b2-AR modulates the expression of numerous prosurvival, invasion, and metastasis genes through multiple signaling cascades (Cole & Sood 2012, Shi et al 2013a.…”

Beta-adrenergic blocking drugs in breast cancer: a perspective review

“…There are three β-AR subtypes, β 1 -AR, β 2 -AR and β 3 -AR, each with specific physiological actions. The expression of β-ARs has been characterized in several breast cancer cell lines [Vandewalle et al 1990;Badino et al 1996;Slotkin et al 2000;Sloan et al 2010;Madden et al 2011;Park et al 2011;Shi et al 2011] as well as in collections of human breast cancer tissue samples [Draoui et al 1991;Powe et al 2011;Shi et al 2011] and in mammary tumours from rodents induced by administration of dimethylbenz(a)anthracene [Marchetti et al 1991] (see Table 1). Studies have shown that these β-ARs are predominantly of the β 2 -adrenergic receptor (β 2 -AR) subtype [Draoui et al 1991;Badino et al 1996;Slotkin et al 2000] and are functionally active, with pharmacological ligation resulting in significant cAMP production [Vandewalle et al 1990;Badino et al 1996;Slotkin et al 2000;Sloan et al 2010;Madden et al 2011].…”

β-Adrenergic Receptors : New Target in Breast Cancer

“…In preclinical studies, researchers had observed the expression of beta-adrenergic receptors in a few breast cancer cell lines and human breast cancer tissue samples (Madden et al, 2011;Park et al, 2011;Powe et al, 2011). Beta-adrenergic receptor signaling had been demonstrated to accelerate angiogenesis through increasing the expression of vascular endothelial growth factor (VEGF) (Lutgendorf et al, 2003;Thaker et al, 2006;Yang et al, 2006;Zhang et al, 2010) and interleukin-6 (IL-6) (Thaker et al, 2006;Sloan et al, 2010), promote breast cancer growth (Cakir et al, 2002;Thaker et al, 2006;Shi et al, 2011), recurrence and metastasis (Benish et al, 2008;Avraham et al, 2010;Sloan et al, 2010) and reduce apoptosis of cancer cells (Sastry et al, 2007;Zhang et al, 2009;Sood et al, 2010;Set al, 2011).…”