Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis
Abstract
Breast cancer metastasis is facilitated by sympathetic nervous system (SNS) activation, but the role for 2-AR, a major class of SNS receptors, has not been elucidated. The goal of this proposal is to characterize the effects of dexmedetomidine (DEX), a highly selective 2-AR agonist, on tumor metastasis in preclinical models of breast cancer. We tested the hypothesis that 2- AR-induced tumor progression is mediated by alterations in fibrillar collagen microstructure as detected by multiphoton second harmonic generation (SHG) imaging. Using 4T1, a metastatic mammary adenocarcinoma in BALB/c mice, 2-AR activation increased metastasis to the lungs in conjunction with elevated tumor SHG-emitting collagen. DEX did not alter metastasis or tumor SHG in immunodeficient BALB/c SCID mice or in MMTV-PyMT mice. In BALB/c mice treated with a 2-AR-selective agonist, increased 4T1 metastasis was also associated with elevated SHG-emitting collagen. These results suggest 1) increased collagen SHG is indicative of elevated metastatic risk; 2) DEX acts via functional T cells to alter collagen SHG; and 3) the effect of DEX may be dependent on the tumor model. At the low, non-sedative dose used here, DEX did not alter sympathetic neurotransmission, confirming that DEX acts through peripheral, post-synaptic 2-AR to modify tumor collagen. Tumor associated fibroblasts (TAF) were isolated to determine if 2 AR activation directly modulates collagen microstructure.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA614114
Entities
People
- Kelley S. Madden
Organizations
- University of Rochester