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

Neoplasia. 2021 Feb;23(2):270-279. doi: 10.1016/j.neo.2020.12.011. Epub 2021 Jan 16.


The opioid crisis of pain medication bears risks from addiction to cancer progression, but little experimental evidence exists. Expression of δ-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.

Keywords: Breast cancer; EMT; Metastasis; Opioid; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Biomarkers
  • Breast Neoplasms / etiology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Disease Susceptibility
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis
  • Oncogene Proteins / metabolism
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / genetics
  • Receptors, Opioid, delta / metabolism*
  • STAT3 Transcription Factor / metabolism*


  • Analgesics, Opioid
  • Biomarkers
  • Oncogene Proteins
  • Receptors, Opioid, delta
  • STAT3 Transcription Factor