BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways
- Date Crossref
- 02/10/2020
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University of Kentucky Department of Statistics pays non établi dans la noticeUniversité ou école supérieure
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Markey Cancer Center pays non établi dans la noticeÉtablissement de santé
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Soochow University Department of Respiratory Medicine pays non établi dans la noticeUniversité ou école supérieure
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First Affiliated Hospital of Soochow University pays non établi dans la noticeÉtablissement de santé
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Nanjing Medical University Department of Oncology pays non établi dans la noticeUniversité ou école supérieure
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China Pharmaceutical University Center of Drug Discovery pays non établi dans la noticeUniversité ou école supérieure
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First Affiliated Hospital of Xi'an Jiaotong University Department of Medical Oncology pays non établi dans la noticeÉtablissement de santé
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University of Science and Technology of China pays non établi dans la noticeUniversité ou école supérieure
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Anhui Provincial Hospital pays non établi dans la noticeÉtablissement de santé
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College of Medicine Department of Pharmacology and Nutritional Sciences pays non établi dans la noticeUniversité ou école supérieure
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The First Affiliated Hospital of University of Science & Technology of China and Provincial Hospital pays non établi dans la noticeUniversité ou école supérieure
Department of Statistics — University of Kentucky, Markey Cancer Center et Department of Respiratory Medicine — Soochow University, avec 8 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.