α2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression.

Donald M Lamkin, Ha Yeon Sung, Gyu Sik Yang, John M David, Jeffrey C Y Ma, Steve W Cole, Erica K Sloan

Psychoneuroendocrinology 2015 Jan

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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 β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-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 α-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 β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology. Copyright © 2014 Elsevier Ltd. All rights reserved.

Citation

Donald M Lamkin, Ha Yeon Sung, Gyu Sik Yang, John M David, Jeffrey C Y Ma, Steve W Cole, Erica K Sloan. α2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression. Psychoneuroendocrinology. 2015 Jan;51:262-70