In breast cancer patients, chronic emotional stress accompanies the physiological toll of the cancer and subsequent therapeutic treatment. There is evidence from breast cancer patients that stress can augment breast tumor growth and recurrence, but the biochemical mechanisms are not understood. Sympathetic nervous system release of the catecholamines norepinephrine and epinephrine and activation of adrenergic receptors constitute a major stress pathway in mice and humans. We have observed sympathetic tyrosine hydroxylase-positive nerve fibers adjacent to blood vessels in breast tumors grown in the mammary fat pad of mice. We have also determined that stimulation of breast cancer cell lines with ss-adrenergic receptor agonists dramatically elevates interleukin-6 (IL-6), a molecule that facilitates tumor angiogenesis, invasion and metastasis. In this proposal, we hypothesize that chronic stress exposure stimulates tumor growth, angiogenesis, and metastasis through activation of the sympathetic nervous system. We will characterize the impact of social isolation, a chronic stressor, on tumor growth and metastasis in a mouse orthotopic breast cancer model (specific aim 1) and in a spontaneously occurring mouse model of breast cancer (specific aim 2). In these experiments, we will determine if ablation of sympathetic innervation or blockade of ss-adrenergic receptors prevent stress-induced alterations in tumor pathogenesis.
In specific aim 3, we will characterize the anatomical relationship between sympathetic innervation and tumor blood vessels in vivo. We will use transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase promoter (TH-EGFP mice) and in vivo imaging with multiphoton laser scanning microscopy (MPLSM) to dynamically monitor the relationship between the tumor vasculature (labeled with tetramethyl rhodamine-dextran (red)) and EGFP-labeled TH+ nerve fibers (green) in a growing tumor. These experiments will define the role of the sympathetic nervous system in stress-induced tumor progression. Pharmacological blockers of the sympathetic nervous system have been proven safe and effective in the treatment of cardiovascular disease, offering the possibility of their rapid application to the improvement of current breast cancer therapies.

Public Health Relevance

Our studies will connect stress exposure and the stress hormones norepinephrine and epinephrine to cancer growth and spread in two mouse models of breast cancer. This work will provide immediate insight into how long-term stress exposure influences breast cancer growth and metastasis, and will lead to additional options for the treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA152777-02
Application #
8100311
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Mc Donald, Paige A
Project Start
2010-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$193,675
Indirect Cost
Name
University of Rochester
Department
Biomedical Engineering
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Madden, Kelley S (2017) Sympathetic neural-immune interactions regulate hematopoiesis, thermoregulation and inflammation in mammals. Dev Comp Immunol 66:92-97
Szpunar, Mercedes J; Belcher, Elizabeth K; Dawes, Ryan P et al. (2016) Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer. Brain Behav Immun 53:223-233
Szpunar, Mercedes J; Burke, Kathleen A; Dawes, Ryan P et al. (2013) The antidepressant desipramine and ?2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev Res (Phila) 6:1262-72
Burke, Ryan M; Madden, Kelley S; Perry, Seth W et al. (2013) Tumor-associated macrophages and stromal TNF-? regulate collagen structure in a breast tumor model as visualized by second harmonic generation. J Biomed Opt 18:86003
Madden, Kelley S; Szpunar, Mercedes J; Brown, Edward B (2013) Early impact of social isolation and breast tumor progression in mice. Brain Behav Immun 30 Suppl:S135-41
Madden, Kelley S; Szpunar, Mercedes J; Brown, Edward B (2011) ýý-Adrenergic receptors (ýý-AR) regulate VEGF and IL-6 production by divergent pathways in high ýý-AR-expressing breast cancer cell lines. Breast Cancer Res Treat 130:747-58