| Summary: | Chronic secretion and exposure to IL-6 proinflammatory cytokine plays a significant
role in tumor promoting inflammation resulting in a feedback loop of persistent activation
of pro-inflammatory signaling and tumor progression. In this study, we determined that
triple negative breast cancer (TNBC) cells secrete high levels of proinflammatory markers
including IL-6, IL-8, VEGF, and higher NF-κB transcription factor activation as
compared to normal breast epithelial cells. The IL-6 cytokine signaling molecules drives
chronic inflammation by inducing the activation of the NF-κΒ cell nuclear
transcription factor pathway. The NF-κΒ activated pathway mediates tumor induced
inflammation by transcribing chemokines/cytokines such as IL-8, VEGF, and IL-6, which in
turn serves to promote tumor progression leading to a feedforward pro-tumor inflammation.
Our focus in this study was to attenuate tumor promoting inflammation and progression by
targeting the highly secreted proinflammatory markers in breast tumor cells including IL-6,
IL-8, and VEGF. We targeted the breast tumor proinflammation by the modulation of the
endocannabinoid system through MGL inhibition using AM4301 and AM9928, and selective CB2
membrane receptor agonist AM1710. AM4301, AM9928, and AM1710 attenuated breast tumor
associated inflammation by reducing pro-inflammatory chemokine/cytokine release including
IL-6, IL-8, and pro-angiogenic mediators including VEGF, and reduced breast cancer cell
proliferation, invasion, and migration.--Author's abstract
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