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Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis

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Annual rept. 30 Sep 2013-29 Sep 2014

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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 BALBc 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 BALBc SCID mice or in MMTV-PyMT mice. In BALBc 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.

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  • Anatomy and Physiology
  • Medicine and Medical Research
  • Pharmacology

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