IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment.
Angiogenesis Inhibitors
/ pharmacology
Animals
Antineoplastic Agents, Immunological
/ immunology
Cell Line, Tumor
Endoplasmic Reticulum Stress
/ drug effects
Endoribonucleases
/ antagonists & inhibitors
Female
Gene Knockout Techniques
Humans
Mice
Mice, SCID
Neovascularization, Pathologic
/ therapy
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
RNA, Messenger
/ genetics
Triple Negative Breast Neoplasms
/ blood supply
Tumor Microenvironment
Vascular Endothelial Growth Factor A
/ antagonists & inhibitors
X-Box Binding Protein 1
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
04
10
2019
revised:
20
02
2020
accepted:
01
04
2020
pubmed:
9
4
2020
medline:
12
11
2020
entrez:
9
4
2020
Statut:
ppublish
Résumé
Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal posttreatment prognosis-implicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance antiangiogenic therapy-previously found to be ineffective in patients with TNBC. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of their ER upon growth
Identifiants
pubmed: 32265225
pii: 0008-5472.CAN-19-3108
doi: 10.1158/0008-5472.CAN-19-3108
pmc: PMC7272310
mid: NIHMS1583293
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Antineoplastic Agents, Immunological
0
RNA, Messenger
0
VEGFA protein, human
0
Vascular Endothelial Growth Factor A
0
X-Box Binding Protein 1
0
XBP1 protein, human
0
ERN1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2368-2379Subventions
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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