?2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression.

ABSTRACT: 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 ?-adrenergic receptors. Catecholamines also signal ?-adrenergic receptors, and greater ?-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of ?-adrenergic receptors can result in elevated catecholamine levels, which may increase ?-adrenergic signaling, because pre-synaptic ?2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of ?-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective ?-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 ?-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective ?2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective ?1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that ?2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of ?-adrenergic signaling on tumor progression-relevant biology.

SUBMITTER: Lamkin DM 

PROVIDER: S-EPMC4406769 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature