PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
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American Association for Cancer Research
2017
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| Online Access: | http://hdl.handle.net/20.500.11937/60223 |
| _version_ | 1848760588132417536 |
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| author | Chen, L. Yuan, Y. Kar, S. Kanchi, M. Arora, S. Kim, J. Koh, P. Yousef, E. Samy, R. Shanmugam, M. Tan, T. Shin, S. Arfuso, Frank Shen, H. Yang, H. Goh, B. Park, J. Gaboury, L. Lobie, P. Sethi, Gautam Lim, L. Kumar, Alan |
| author_facet | Chen, L. Yuan, Y. Kar, S. Kanchi, M. Arora, S. Kim, J. Koh, P. Yousef, E. Samy, R. Shanmugam, M. Tan, T. Shin, S. Arfuso, Frank Shen, H. Yang, H. Goh, B. Park, J. Gaboury, L. Lobie, P. Sethi, Gautam Lim, L. Kumar, Alan |
| author_sort | Chen, L. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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?. 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? both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPAR? ligands. Mechanistically, we show for the first time PPAR?-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?-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? chemotherapy trials. Mol Cancer Ther; 16(11); 2528-42. ©2017 AACR. |
| first_indexed | 2025-11-14T10:18:09Z |
| format | Journal Article |
| id | curtin-20.500.11937-60223 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:18:09Z |
| publishDate | 2017 |
| publisher | American Association for Cancer Research |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-602232019-05-22T06:49:12Z PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers Chen, L. Yuan, Y. Kar, S. Kanchi, M. Arora, S. Kim, J. Koh, P. Yousef, E. Samy, R. Shanmugam, M. Tan, T. Shin, S. Arfuso, Frank Shen, H. Yang, H. Goh, B. Park, J. Gaboury, L. Lobie, P. Sethi, Gautam Lim, L. Kumar, Alan 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?. 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? both in vitro and in vivo and it has a predictive value in determining chemosensitivity to PPAR? ligands. Mechanistically, we show for the first time PPAR?-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?-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? chemotherapy trials. Mol Cancer Ther; 16(11); 2528-42. ©2017 AACR. 2017 Journal Article http://hdl.handle.net/20.500.11937/60223 10.1158/1535-7163.MCT-16-0739 American Association for Cancer Research restricted |
| spellingShingle | Chen, L. Yuan, Y. Kar, S. Kanchi, M. Arora, S. Kim, J. Koh, P. Yousef, E. Samy, R. Shanmugam, M. Tan, T. Shin, S. Arfuso, Frank Shen, H. Yang, H. Goh, B. Park, J. Gaboury, L. Lobie, P. Sethi, Gautam Lim, L. Kumar, Alan PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title | PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title_full | PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title_fullStr | PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title_full_unstemmed | PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title_short | PPARγ Ligand–induced Annexin A1 Expression Determines Chemotherapy Response via Deubiquitination of Death Domain Kinase RIP in Triple-negative Breast Cancers |
| title_sort | pparγ ligand–induced annexin a1 expression determines chemotherapy response via deubiquitination of death domain kinase rip in triple-negative breast cancers |
| url | http://hdl.handle.net/20.500.11937/60223 |