Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05763-8
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Funding
- NUI Galway
- Irish Government's Programme for Research in Third Level Institutions, Cycles 4 & 5, National Development Plan 2007-2013
- Breast Cancer Campaign grant [2010NovPR13, 2015MaySP550]
- Health Research Board [HRA-POR-2014-643]
- Belgium Grant [IAP 7/32]
- Science Foundation Ireland (SFI) grant - European Regional Development Fund [13/RC/2073]
- SFI Starting Investigator Grant [15/SIRG/3528]
- EU H2020 MSCA [ITN-675448, RISE-734749]
- Institut National du Cancer (INCa) [PLBIO: 2017-148]
- Irish Cancer Society Scholarship [CRS11CLE]
- Thomas Crawford Hayes Funds of NUIG
- Irish Research Council Employment Based Programme Scholarship Scheme [BPPG/2014/57]
- Irish Research Council Fellowship [GOIPD/2014/53]
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Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGF beta 2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
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