Luxi Chen1,2,3, Yi Yuan1, Shreya Kar1,2, Madhu M. Kanchi1, Suruchi Arora4, Ji E. Kim1, Pei F. Koh1,2, Einas Yousef5,6, Ramar P. Samy4, Muthu K. Shanmugam2, Tuan Z. Tan1, Sung W. Shin7, Frank Arfuso8, Han M. Shen4,9, Henry Yang1, Boon C. Goh1,2,10,11, Joo I. Park7, Louis Gaboury5, Peter E. Lobie1,2,11,12, Gautam Sethi2,13, Lina HK. Lim4,9,14,*, Alan P. Kumar1,2,11,15,16,*.
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore;
2 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
4 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;
3 Department of Chemistry and Biochemistry, School of Natural Sciences & Mathematics, The University of Texas at Dallas, Texas, USA;
5 Institute for Research in Immunology and Cancer, Universite de Montreal, Canada;
6 Department of Histology, Faculty of Medicine, Menoufia University, Menoufia, Egypt;
7 Department of Biochemistry, Dong-A University, College of Medicine, Busan, South Korea;
8 Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia;
9 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore;
10 Department of Haematology-Oncology, National University Health System, Singapore;
11 National University Cancer Institute, National University Health System, Singapore;
12 Tsinghua Berkeley Shenzhen Institute and Division of Life Science and Health, Tsinghua University Graduate School, Shenzhen, P. R. China;
13 School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia;
14 NUS Immunology Program, National University of Singapore, Singapore;
15 Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth WA, Australia;
16 Department of Biological Sciences, University of North Texas, Denton, Texas, USA.
* Corresponding authors:
Lina H. K. Lim, Ph.D., Department of Physiology& NUS Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117597, Phone: (65) 6516-5515; Fax: (65) 6778-8161; Email: email@example.com;
Alan Prem Kumar, Ph.D., Cancer Science Institute of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore 117599. Phone: (65) 6516-5456; Fax (65) 6873-9664; Email: firstname.lastname@example.org; email@example.com.
Metastatic breast cancer is still remain 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 has 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 which model the TNBC subtype, we observed a strong positive correlation between expression of ANXA1 and Peroxisome Proliferator-Activated Receptor gamma (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 invivo and it has a predictive value in determining chemo-sensitivity 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 towards 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. Hitherto, presenting itself both as an inclusion criterion for patient selection and surrogate marker for drug response in future PPARγ chemotherapy trials.