title: Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer.
abstract: Activation of the sympathetic nervous system (SNS) drives breast cancer progression in preclinical breast cancer models, but it has yet to be established if neoplastic and stromal cells residing in the tumor are directly targeted by locally released norepinephrine (NE). In murine orthotopic and spontaneous mammary tumors, tyrosine hydroxylase (TH)+ sympathetic nerves were limited to the periphery of the tumor. No TH+ staining was detected deeper within these tumors, even in regions with a high density of blood vessels. NE concentration was much lower in tumors compared to the more densely innervated spleen, reflecting the relative paucity of tumor TH+ innervation. Tumor and spleen NE concentration decreased with increased tissue mass. In mice treated with the neurotoxin 6-hydroxydopamine (6-OHDA) to selectively destroy sympathetic nerves, tumor NE concentration was reduced approximately 50%, suggesting that the majority of tumor NE is derived from local sympathetic nerves. To evaluate NE utilization, NE turnover in orthotopic 4T1 mammary tumors was compared to spleen under baseline and stress conditions. In non-stressed mice, NE turnover was equivalent between tumor and spleen. In mice exposed to a stressor, tumor NE turnover was increased compared to spleen NE turnover, and compared to non-stressed tumor NE turnover. Together, these results demonstrate that NE in mammary tumors is derived from local sympathetic nerves that synthesize and metabolize NE. However, differences between spleen and tumor NE turnover with stressor exposure suggest that sympathetic NE release is regulated differently within the tumor microenvironment compared to the spleen. Local mammary tumor sympathetic innervation, despite its limited distribution, is responsive to stressor exposure and therefore can contribute to stress-induced tumor progression.
authors.affiliation: Department of Pathology, School of Medicine and Dentistry, University of Rochester, Rochester, NY USA.
authors.forename: Mercedes J
authors.initials: MJ
authors.lastname: Szpunar
authors.affiliation: Translational Biomedical Science Program, School of Medicine and Dentistry, University of Rochester, Rochester, NY USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Belcher
authors.affiliation: Neuroscience Graduate Program, School of Medicine and Dentistry, University of Rochester, Rochester, NY USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Dawes
authors.affiliation: Department of Biomedical Engineering, School of Medicine and Dentistry, University of Rochester, Rochester, NY USA.
authors.forename: Kelley S
authors.initials: KS
authors.lastname: Madden
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D008321:Mammary Glands, Animal / Q000294:innervation*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009638:Norepinephrine / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine
keywords: Breast cancer; Chemical sympathectomy; Norepinephrine; Norepinephrine turnover; Sympathetic nervous system