TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Logue, Susan E.
A1  - McGrath, Eoghan P.
A1  - Cleary, Patricia
A1  - Greene, Stephanie
A1  - Mnich, Katarzyna
A1  - Almanza, Aitor
A1  - Chevet, Eric
A1  - Dwyer, Róisín M.
A1  - Oommen, Anup
A1  - Legembre, Patrick
A1  - Godey, Florence
A1  - Madden, Emma C.
A1  - Leuzzi, Brian
A1  - Obacz, Joanna
A1  - Zeng, Qingping
A1  - Patterson, John B.
A1  - Jäger, Richard
A1  - Gorman, Adrienne M.
A1  - Samali, Afshin
T1  - Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy
JF  - Nature Communications
N2  - 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 TGFβ2 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.
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-39907
SN  - 2041-1723
SS  - 2041-1723
U6  - https://doi.org/10.1038/s41467-018-05763-8
DO  - https://doi.org/10.1038/s41467-018-05763-8
PM  - 30111846
VL  - 9
SP  - 14
S1  - 14
PB  - Nature Publishing Group
ER  -