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IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel

Author

Listed:
  • Zhen Ning Wee

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Siti Maryam J. M. Yatim

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Vera K Kohlbauer

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Min Feng

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Jian Yuan Goh

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Yi Bao

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Puay Leng Lee

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Songjing Zhang

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research))

  • Pan Pan Wang

    (First Affiliated Hospital, Jinan University
    Cancer Research Institute, Jinan University)

  • Elgene Lim

    (The Kinghorn Cancer Center, Garvan Institute of Medical Research)

  • Wai Leong Tam

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
    Cancer Science Institute, National University of Singapore)

  • Yu Cai

    (Cancer Research Institute, Jinan University
    School of Pharmacy, Jinan University)

  • Henrik J Ditzel

    (Institute of Molecular Medicine, University of Southern Denmark
    Odense University Hospital)

  • Dave S. B. Hoon

    (John Wayne Cancer Institute, Santa Monica, California 90404, USA)

  • Ern Yu Tan

    (Tan Tock Seng Hospital)

  • Qiang Yu

    (Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research)
    Cancer Research Institute, Jinan University
    Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
    Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore 169857, Singapore)

Abstract

Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-negative breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-κB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance.

Suggested Citation

  • Zhen Ning Wee & Siti Maryam J. M. Yatim & Vera K Kohlbauer & Min Feng & Jian Yuan Goh & Yi Bao & Puay Leng Lee & Songjing Zhang & Pan Pan Wang & Elgene Lim & Wai Leong Tam & Yu Cai & Henrik J Ditzel &, 2015. "IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel," Nature Communications, Nature, vol. 6(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9746
    DOI: 10.1038/ncomms9746
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    Cited by:

    1. Shijun Ma & Yue Zhao & Wee Chyan Lee & Li-Teng Ong & Puay Leng Lee & Zemin Jiang & Gokce Oguz & Zhitong Niu & Min Liu & Jian Yuan Goh & Wenyu Wang & Matias A. Bustos & Sidse Ehmsen & Adaikalavan Ramas, 2022. "Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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