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BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways
PURPOSE: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a tra...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716866/ https://www.ncbi.nlm.nih.gov/pubmed/33006750 http://dx.doi.org/10.1007/s13402-020-00537-1 |
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author | Zhang, Yang Xu, Bingwei Shi, Junfeng Li, Jieming Lu, Xinlan Xu, Li Yang, Helen Hamad, Nevean Wang, Chi Napier, Dana He, Shuixiang Liu, Chunming Liu, Zeyi Qian, Hai Chen, Li Wei, Xiaowei Zheng, Xucai Huang, Jian-An Thibault, Olivier Craven, Rolf Wei, Dongping Pan, Yueyin Zhou, Binhua P. Wu, Yadi Yang, Xiuwei H. |
author_facet | Zhang, Yang Xu, Bingwei Shi, Junfeng Li, Jieming Lu, Xinlan Xu, Li Yang, Helen Hamad, Nevean Wang, Chi Napier, Dana He, Shuixiang Liu, Chunming Liu, Zeyi Qian, Hai Chen, Li Wei, Xiaowei Zheng, Xucai Huang, Jian-An Thibault, Olivier Craven, Rolf Wei, Dongping Pan, Yueyin Zhou, Binhua P. Wu, Yadi Yang, Xiuwei H. |
author_sort | Zhang, Yang |
collection | PubMed |
description | PURPOSE: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. METHODS: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. RESULTS: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G(+) myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. CONCLUSION: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13402-020-00537-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7716866 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-77168662020-12-04 BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways Zhang, Yang Xu, Bingwei Shi, Junfeng Li, Jieming Lu, Xinlan Xu, Li Yang, Helen Hamad, Nevean Wang, Chi Napier, Dana He, Shuixiang Liu, Chunming Liu, Zeyi Qian, Hai Chen, Li Wei, Xiaowei Zheng, Xucai Huang, Jian-An Thibault, Olivier Craven, Rolf Wei, Dongping Pan, Yueyin Zhou, Binhua P. Wu, Yadi Yang, Xiuwei H. Cell Oncol (Dordr) Original Paper PURPOSE: Stemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC. METHODS: Two independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model. RESULTS: We found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G(+) myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation. CONCLUSION: Based on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13402-020-00537-1) contains supplementary material, which is available to authorized users. Springer Netherlands 2020-10-02 2020 /pmc/articles/PMC7716866/ /pubmed/33006750 http://dx.doi.org/10.1007/s13402-020-00537-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Paper Zhang, Yang Xu, Bingwei Shi, Junfeng Li, Jieming Lu, Xinlan Xu, Li Yang, Helen Hamad, Nevean Wang, Chi Napier, Dana He, Shuixiang Liu, Chunming Liu, Zeyi Qian, Hai Chen, Li Wei, Xiaowei Zheng, Xucai Huang, Jian-An Thibault, Olivier Craven, Rolf Wei, Dongping Pan, Yueyin Zhou, Binhua P. Wu, Yadi Yang, Xiuwei H. BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title | BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title_full | BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title_fullStr | BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title_full_unstemmed | BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title_short | BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
title_sort | brd4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716866/ https://www.ncbi.nlm.nih.gov/pubmed/33006750 http://dx.doi.org/10.1007/s13402-020-00537-1 |
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