BRD4 modulates vulnerability of triple-negative breast cancer to targeting of integrin-dependent signaling pathways.

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.

• Authors: Yang Zhang, Bingwei Xu, Junfeng Shi, Jieming Li, Xinlan Lu, Li Xu, Helen Yang, Nevean Hamad, Chi Wang, Dana Napier, Shuixiang He, Chunming Liu, Zeyi Liu, Hai Qian, Li Chen, Xiaowei Wei, Xucai Zheng, Jian-An Huang, Olivier Thibault, Rolf Craven, Dongping Wei, Yueyin Pan, Binhua P Zhou, Yadi Wu, Xiuwei H Yang
• Journal: Cellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 43 Issue 6 Pg. 1049-1066 (Dec 2020) ISSN: 2211-3436 [Electronic] Netherlands
• PMID: 33006750 (Publication Type: Journal Article)

Chemical References

• (+)-JQ1 compound
• Azepines
• BRD4 protein, human
• Bcl-2-Like Protein 11
• Benzamides
• Cell Cycle Proteins
• Integrins
• Proto-Oncogene Proteins c-myc
• Pyrazines
• RNA, Messenger
• Sulfonamides
• Transcription Factors
• Triazoles
• defactinib
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Azepines (pharmacology)
• Bcl-2-Like Protein 11 (metabolism)
• Benzamides (pharmacology)
• Cell Cycle Proteins (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Focal Adhesion Protein-Tyrosine Kinases (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Genome, Human
• Humans
• Integrins (metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Pyrazines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Transcription Factors (metabolism)
• Triazoles (pharmacology)
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)