Opioids drive breast cancer metastasis through the δ-opioid receptor and oncogenic STAT3.
Analgesics, Opioid
/ pharmacology
Animals
Biomarkers
Breast Neoplasms
/ etiology
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
STAT3 Transcription Factor
/ metabolism
Breast cancer
EMT
Metastasis
Opioid
STAT3
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
10
05
2020
revised:
25
12
2020
accepted:
29
12
2020
pubmed:
20
1
2021
medline:
13
10
2021
entrez:
19
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33465556
pii: S1476-5586(21)00001-4
doi: 10.1016/j.neo.2020.12.011
pmc: PMC7815495
pii:
doi:
Substances chimiques
Analgesics, Opioid
0
Biomarkers
0
Oncogene Proteins
0
Receptors, Opioid, delta
0
STAT3 Transcription Factor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
270-279Subventions
Organisme : Austrian Science Fund FWF
ID : I 4157
Pays : Austria
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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