BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways
Yang Zhang1,2, Bingwei Xu1, Junfeng Shi3
1Department of Pharmacology and Nutritional Sciences, Department of Molecular and Cellular Biochemistry, and Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA.
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.
Insights
Co-inhibiting the BRD4/c-Myc and integrin/FAK pathways shows therapeutic potential for triple-negative breast cancer (TNBC). This dual-targeting strategy, using JQ1 and VS-6063, effectively reduced tumor growth and induced cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Triple-negative breast cancer (TNBC) presents significant therapeutic challenges due to its genetic and epigenetic heterogeneity.
- Identifying novel therapeutic targets is crucial for improving clinical outcomes in TNBC patients.
Purpose of the Study:
- To investigate the therapeutic potential of simultaneously inhibiting the integrin-dependent signaling pathway and BRD4 in TNBC.
- To explore the combined efficacy of targeting BRD4/c-Myc and integrin/FAK pathways for TNBC treatment.
Main Methods:
- Bioinformatic and immunohistochemical (IHC) analyses of patient cohorts to identify cancer drivers.
- In vitro studies using TNBC cell lines and in vivo xenograft models to assess therapeutic efficacy.
- Utilized chemical inhibitors, RNAi/CRISPR/Cas9, and protein kinase arrays to elucidate biological mechanisms.
Main Results:
- Amplification of chromosome 8q24, co-occurring with c-Myc and FAK upregulation, was observed in ~20% of TNBC tumors and correlated with poor patient survival.
- TNBC cell lines showed significant vulnerability to the combined inhibition of BRD4 (JQ1) and integrin/FAK (VS-6063).
- Combined JQ1 and VS-6063 treatment demonstrated cooperative inhibition of tumor growth, reduced immunosuppressive myeloid cells, and induced apoptosis via multiple signaling pathways.
Conclusions:
- The BRD4/c-Myc and integrin/FAK pathways are concurrently activated in TNBC and contribute to tumor progression and poor outcomes.
- Combined inhibition of these pathways represents a promising synthetic lethal therapeutic strategy for TNBC.
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