Opioids drive breast cancer metastasis through the δ-opioid receptor and oncogenic STAT3

The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental evidence exists. Expression of delta-opioid receptors (DORs) correlates with poor prognosis for breast cancer patients, but mechanistic insights into oncogenic signaling mechanisms of opioid-triggered cancer progression are lacking. We show that orthotopic transplant models using human or murine breast cancer cells displayed enhanced metastasis upon opioid-induced DOR stimulation. Interestingly, opioid-exposed breast cancer cells showed enhanced migration and strong STAT3 activation, which was efficiently blocked by a DOR-antagonist. Furthermore, opioid treatment resulted in down-regulation of E-Cadherin and increased expression of epithelial-mesenchymal transition markers. Notably, STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced breast cancer cell metastasis and migration in vitro and in vivo. We conclude on a novel mechanism whereby opioid-triggered breast cancer metastasis occurs via oncogenic JAK1/2-STAT3 signaling to promote epithelial-mesenchymal transition. These findings emphasize the importance of selective and restricted opioid use, as well as the need for safer pain medication that does not activate these oncogenic pathways.

Automated summary

Pain medication abuse poses risks for cancer progression, with opioid-induced breast cancer metastasis involving oncogenic JAK1/2-STAT3 signaling and promoting epithelial-mesenchymal transition. It highlights the importance of selective and restricted opioid use and the development of safer pain medication that does not activate oncogenic pathways.