Abstract
PurposeStemming 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.MethodsTwo 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.ResultsWe 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.ConclusionBased 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.
Highlights
Triple-negative breast cancer (TNBC) remains one of the deadliest breast cancer subtypes, as patients carrying this disease are largely dependent on systemic chemotherapies and undergo rapid tumor progression and recurrence [1,2,3]
The c-Myc and focal adhesion kinase (FAK) loci are adjacently situated in the chromosome 8q24 region (8q24.21 and 8q24.30, respectively), and their elevated mRNA expression correlated with a poor patient survival (Fig. S1A), consistent with recent studies [17, 39]
These data suggest a strong link between 8q24 region-based malignancy and co-upregulation of FAK and c-Myc
Summary
Triple-negative breast cancer (TNBC) remains one of the deadliest breast cancer subtypes, as patients carrying this disease are largely dependent on systemic chemotherapies and undergo rapid tumor progression and recurrence [1,2,3]. There is growing evidence that deregulation of the chromosome 8q24 region denotes a distinct class of TNBC [4, 8] This genomic anomaly is characterized by a stretch of genes being co-amplified in primary tumors and is frequently accompanied by hyperactivation of the c-Myc oncogene [5, 9]. It was found that c-Myc activity was dependent on interaction between the bromodomain of BRD4 and acetyl groups of transcription factors within RNA polymerase II-organized complexes [13]. This interaction appears targetable by small molecule inhibitors, like JQ1 and BET-762 [14, 15]. The BRD4-c-Myc axis drives tumor development, and serves as a source of promising targets for mitigating 8q24 amplification-associated malignancy in breast cancer
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