alpha(2)-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of beta-adrenergic receptors. Catecholamines also signal alpha-adrenergic receptors, and greater alpha-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of alpha-adrenergic receptors can result in elevated catecholamine levels, which may increase beta-adrenergic signaling, because pre-synaptic alpha(2)-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of alpha-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231 HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective alpha-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective beta-blocker propranolol inhibited the effect of phentolarnine on breast cancer progression. Selective alpha(2)-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective alpha(1)-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that alpha(2)-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of beta-adrenergic signaling on tumor progression-relevant biology. (C) 2014 Elsevier Ltd. All rights reserved.