Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors

Aditi S. Bapat; Christine H. O’Connor; Kathryn L. Schwertfeger

doi:10.1038/s41598-023-32321-0

Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors

Aditi S. Bapat, Christine H. O’Connor, Kathryn L. Schwertfeger

Research output: Contribution to journal › Article › peer-review

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Abstract

Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.

Original language	English (US)
Article number	5349
Journal	Scientific reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-32321-0
State	Published - Dec 2023

Bibliographical note

Funding Information:
The authors would like to thank Dr. Jeffrey Rosen (Baylor College of Medicine) and Dr. Thomas Griffith (University of Minnesota) for providing tumor cell lines. This research received histology assistance from the University of Minnesota’s Biorepository and Laboratory Services program and was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. Research in this publication was supported by NIH funding R01HD95858, R01CA265004, R01CA215052 and DOD funding BC191153 to KLS. The content is responsibility of the authors and does not represent the official views of the National Institute of Health or the Department of Defense.

Funding Information:
The authors would like to thank Dr. Jeffrey Rosen (Baylor College of Medicine) and Dr. Thomas Griffith (University of Minnesota) for providing tumor cell lines. This research received histology assistance from the University of Minnesota’s Biorepository and Laboratory Services program and was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. Research in this publication was supported by NIH funding R01HD95858, R01CA265004, R01CA215052 and DOD funding BC191153 to KLS. The content is responsibility of the authors and does not represent the official views of the National Institute of Health or the Department of Defense.

Publisher Copyright:
© 2023, The Author(s).

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors",

abstract = "Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.",

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note = "Funding Information: The authors would like to thank Dr. Jeffrey Rosen (Baylor College of Medicine) and Dr. Thomas Griffith (University of Minnesota) for providing tumor cell lines. This research received histology assistance from the University of Minnesota{\textquoteright}s Biorepository and Laboratory Services program and was supported by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grant UL1TR002494. Research in this publication was supported by NIH funding R01HD95858, R01CA265004, R01CA215052 and DOD funding BC191153 to KLS. The content is responsibility of the authors and does not represent the official views of the National Institute of Health or the Department of Defense. Funding Information: The authors would like to thank Dr. Jeffrey Rosen (Baylor College of Medicine) and Dr. Thomas Griffith (University of Minnesota) for providing tumor cell lines. This research received histology assistance from the University of Minnesota{\textquoteright}s Biorepository and Laboratory Services program and was supported by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grant UL1TR002494. Research in this publication was supported by NIH funding R01HD95858, R01CA265004, R01CA215052 and DOD funding BC191153 to KLS. The content is responsibility of the authors and does not represent the official views of the National Institute of Health or the Department of Defense. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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N2 - Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.

AB - Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-κB signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-κB pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies.

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Targeting the NF-κB pathway enhances responsiveness of mammary tumors to JAK inhibitors

Abstract

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PubMed: MeSH publication types

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