Peer-Reviewed Journal Details
Mandatory Fields
Gupta, A;Hossain, MM;Miller, N;Kerin, M;Callagy, G;Gupta, S
2016
November
Oncogene
NCOA3 coactivator is a transcriptional target of XBP1 and regulates PERK-eIF2 alpha-ATF4 signalling in breast cancer
Published
Altmetric: 7WOS: 8 ()
Optional Fields
UNFOLDED PROTEIN RESPONSE STEROID-RECEPTOR COACTIVATOR-3 ENDOPLASMIC-RETICULUM STRESS CELL FATE DECISIONS ER STRESS TRANSLATIONAL REGULATION MESSENGER-RNA PERK ACTIVATION EXPRESSION
35
5860
5871
XBP1 is a multitasking transcription factor and a key component of the unfolded protein response (UPR). Despite the wealth of knowledge about the role of XBP1 in luminal/ER-positive breast cancer, not much is known about the effectors of XBP1 in this context. Here we show that NCOA3 is a transcriptional target of XBP1. We observed increased expression of NCOA3 during conditions of UPR and oestrogen (E2) stimulation. Further investigations revealed a role for the IRE1-XBP1 axis in the induction of NCOA3 during UPR and oestrogen signalling. We identify a novel role for NCOA3 in activation of PERK-ATF4 axis during UPR where knockdown of NCOA3 compromised the optimal activation of the PERK-ATF4 pathway. We found that NCOA3 is required for induction of XBP1 during E2 stimulation and uncover a positive feedback regulatory loop that maintains high levels of NCOA3 and XBP1 in breast cancer. Furthermore, upregulated NCOA3 was required for XBP1-mediated resistance to antihormonal agents. Increased expression of NCOA3 was associated with poor prognosis and higher levels of XBP1-S in breast cancer tissues. Our results uncover a novel steroid hormone-independent role for NCOA3 in UPR signalling. Further we identify a positive feedback regulatory loop consisting of XBP1 and NCOA3 that maintains high levels of NCOA3 and XBP1 expression in breast cancer tissues. Taken together our data identify XBP1-NCOA3 axis that regulates cell fate decisions in ER-positive breast cancer cells.
0950-9232
10.1038/onc.2016.121
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