IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment.

Authors

• Jonathan M Harnoss
• Adrien Le Thomas
• Mike Reichelt
• Ofer Guttman
• Thomas D Wu
• Scot A Marsters
• Anna Shemorry
• David A Lawrence
• David Kan
• Ehud Segal
• Mark Merchant
• Klara Totpal
• Lisa M Crocker
• Kathryn Mesh
• Monika Dohse
• Margaret Solon
• Zora Modrusan
• Joachim Rudolph
• Hartmut Koeppen
• Peter Walter
• Avi Ashkenazi

Publication/Presentation Date

6-1-2020

Abstract

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

Volume

80

Issue

11

First Page

2368

Last Page

2379

ISSN

1538-7445

Published In/Presented At

Harnoss, J. M., Le Thomas, A., Reichelt, M., Guttman, O., Wu, T. D., Marsters, S. A., Shemorry, A., Lawrence, D. A., Kan, D., Segal, E., Merchant, M., Totpal, K., Crocker, L. M., Mesh, K., Dohse, M., Solon, M., Modrusan, Z., Rudolph, J., Koeppen, H., Walter, P., … Ashkenazi, A. (2020). IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment. Cancer research, 80(11), 2368–2379. https://doi.org/10.1158/0008-5472.CAN-19-3108

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

32265225

Department(s)

Administration and Leadership

Document Type

Article