Emotional stress activates the sympathetic nervous system (SNS) and release of the
neurotransmitter norepinephrine to promote
breast tumor pathogenesis. We demonstrate here that the metastatic mammary
adenocarcinoma cell line 4T1 does not express functional
adrenergic receptors (AR), the receptors activated by
norepinephrine, yet stimulation of
adrenergic receptor in vivo altered 4T1
tumor progression in vivo. Chronic treatment with the
antidepressant desipramine (DMI) to inhibit
norepinephrine reuptake increased 4T1
tumor growth but not
metastasis. Treatment with a highly selective α2-adrenergic receptor agonist,
dexmedetomidine (DEX), increased
tumor growth and
metastasis. Neither
isoproterenol (ISO), a β-AR agonist, nor
phenylephrine, an α1-AR agonist, altered
tumor growth or
metastasis. Neither DMI- nor DEX-induced
tumor growth was associated with increased angiogenesis. In DMI-treated mice,
tumor VEGF,
IL-6, and the prometastatic
chemokines RANTES,
M-CSF, and MIP-2 were reduced.
Tumor collagen microstructure was examined using second harmonic generation (SHG), a nonabsorptive optical scattering process to highlight
fibrillar collagen. In DMI- and DEX-treated mice, but not ISO-treated mice,
tumor SHG was significantly altered without changing
fibrillar collagen content, as detected by immunofluorescence. These results demonstrate that α2-AR activation can promote
tumor progression in the absence of direct sympathetic input to
breast tumor cells. The results also suggest that SNS activation may regulate
tumor progression through alterations in the extracellular matrix, with outcome dependent on the combination of
adrenergic receptor activated. These results underscore the complexities underlying SNS regulation of
breast tumor pathogenesis, and suggest that the
therapeutic use of
adrenergic receptor blockers,
tricyclic antidepressants, and
adrenergic receptor agonists must be approached cautiously in patients with
breast cancer.