Targeting breast cancer proinflammation and progression via CB2 receptors activation and NAAA enzyme inhibition

• Online Access: http://hdl.handle.net/2047/D20416551

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