title: α2-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 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.
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA. Electronic address: dlamkin@ucla.edu.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Lamkin
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ha Yeon
authors.initials: HY
authors.lastname: Sung
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors.forename: Gyu Sik
authors.initials: GS
authors.lastname: Yang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: David
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jeffrey C Y
authors.initials: JC
authors.lastname: Ma
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; UCLA Molecular Biology Institute, Los Angeles, CA 90095, USA.
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
authors.affiliation: Cousins Center for PNI, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Department of Cancer Anaesthesia and Pain Medicine, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Sloan
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D011224:Prazosin / Q000494:pharmacology; D012149:Restraint, Physical; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000473:pathology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D001572:Benzofurans; D007093:Imidazoles; C062597:efaroxan; D011224:Prazosin
keywords: Bioluminescent imaging; Breast cancer; Catecholamines; Metastasis; Restraint stress; Sympathetic nervous system; α-Adrenergic receptor