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Title: PPARγ Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers.
Authors: Chen, Luxi 
Yuan, Yi
Kar, Shreya
Kanchi, Madhu M 
Arora, Suruchi
Kim, Ji E
Koh, Pei F 
Yousef, Einas
Samy, Ramar P 
Shanmugam, Muthu K 
Tuan Z 
Shin, Sung W
Arfuso, Frank
Shen, Han M 
Yang, Henry
Goh, Boon C 
Park, Joo I
Gaboury, Louis
Lobie, Peter E 
Sethi, Gautam 
Lim, Lina HK 
Kumar, Alan P 
Keywords: Animals
Annexin A1
Caspase 8
Cell Proliferation
Death Domain
Deubiquitinating Enzymes
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Inhibitor of Apoptosis Proteins
MCF-7 Cells
Neoplasm Metastasis
Nuclear Pore Complex Proteins
PPAR gamma
RNA-Binding Proteins
Triple Negative Breast Neoplasms
Xenograft Model Antitumor Assays
Issue Date: Nov-2017
Citation: Chen, Luxi, Yuan, Yi, Kar, Shreya, Kanchi, Madhu M, Arora, Suruchi, Kim, Ji E, Koh, Pei F, Yousef, Einas, Samy, Ramar P, Shanmugam, Muthu K, Tuan Z, Shin, Sung W, Arfuso, Frank, Shen, Han M, Yang, Henry, Goh, Boon C, Park, Joo I, Gaboury, Louis, Lobie, Peter E, Sethi, Gautam, Lim, Lina HK, Kumar, Alan P (2017-11). PPARγ Ligand-induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers.. Mol Cancer Ther 16 (11) : 2528-2542. ScholarBank@NUS Repository.
Abstract: 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 PPARγ. 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 PPARγ both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPARγ ligands. Mechanistically, we show for the first time PPARγ-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 PPARγ-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 PPARγ chemotherapy trials. Mol Cancer Ther; 16(11); 2528-42. ©2017 AACR.
Source Title: Mol Cancer Ther
ISSN: 15357163
DOI: 10.1158/1535-7163.MCT-16-0739
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