Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 11, Pages 2528-2542Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0739
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Funding
- National Medical Research Council of Singapore
- NCIS
- Singapore NMRC Clinician Scientist IRG
- National Research Foundation Singapore
- Singapore Ministry of Education under Research Centers of Excellence Initiative
- NUHS
- Ministry of Education
- Korea Science and Engineering Foundation (KOSEF) - Korea government (MEST)
- Singapore Ministry of Education
- National Medical Research Council Singapore (NMRC)
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Metastatic breast cancer is still incurable so far; new specifically targeted and more effective therapies for triple-negative breast cancer (TNBC) are required in the clinic. In this study, our clinical data have established that basal and claudin-low subtypes of breast cancer (TNBC types) express significantly higher levels of Annexin A1 (ANXA1) with poor survival outcomes. Using human cancer cell lines that model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and PPAR gamma. A similar correlation between these two markers was also established in our clinical breast cancer patients' specimens. To establish a link between these two markers in TNBC, we show de novo expression of ANXA1 is induced by activation of PPAR gamma both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPAR gamma ligands. Mechanistically, we show for the first time PPAR gamma-induced ANXA1 protein directly interacts with receptor interacting protein-1 (RIP1), promoting its deubiquitination and thereby activating the caspase-8-dependent death pathway. We further identified this underlying mechanism also involved a PPAR gamma-induced ANXA1-dependent autoubiquitination of cIAP1, the direct E3 ligase of RIP1, shifting cIAP1 toward proteosomal degradation. Collectively, our study provides first insight for the suitability of using drug-induced expression of ANXA1 as a new player in RIP1-induced death machinery in TNBCs, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPAR gamma chemotherapy trials. (C) 2017 AACR.
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