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bioRxiv · 10.1101/443663

Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial mesenchymal transition

Tripolt, S.·Knab, V. M.·Neubauer, H. A.·Elmer, D. P.·Aberger, F.·Moriggl, R.·Fux, D. A.
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Abstract

The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental facts exist. Expression of {delta}-opioid receptors (DORs) correlates with poor prognosis for breast cancer (BCa) patients, but mechanism and genetic/pharmacologic proof of key changes in opioid-triggered cancer biology are lacking. We show that oncogenic STAT3 signaling and E-Cadherin downregulation are triggered by opioid-ligated DORs, promoting metastasis. Human and murine transplanted BCa cells (MDA-MB-231, 4T1) displayed enhanced metastasis upon opioid-induced DOR stimulation, and DOR-antagonist blocked metastasis. Opioid-exposed BCa cells showed enhanced migration, STAT3 activation, down-regulation of E-Cadherin and expression of epithelial-mesenchymal transition (EMT) markers. STAT3 knockdown or upstream inhibition through the JAK1/2 kinase inhibitor ruxolitinib prevented opioid-induced BCa cell metastasis and migration. We conclude that opioids trigger metastasis through oncogenic JAK1/2-STAT3 signaling.

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Tripolt, S., Knab, V. M., Neubauer, H. A., Elmer, D. P., Aberger, F., Moriggl, R., Fux, D. A.. 2018-10-15. Opioids trigger breast cancer metastasis through E-Cadherin downregulation and STAT3 activation promoting epithelial mesenchymal transition. https://doi.org/10.1101/443663

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