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- Title
BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways.
- Authors
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
- Abstract
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.
- Subjects
TRIPLE-negative breast cancer; INTEGRINS; SUPPRESSOR cells; PROTEIN microarrays; TRANSCRIPTION factors
- Publication
Cellular Oncology (2211-3428), 2020, Vol 43, Issue 6, p1049
- ISSN
2211-3428
- Publication type
Article
- DOI
10.1007/s13402-020-00537-1