| First Author | Wu SY | Year | 2020 |
| Journal | Mol Cell | Volume | 78 |
| Issue | 6 | Pages | 1114-1132.e10 |
| PubMed ID | 32446320 | Mgi Jnum | J:297109 |
| Mgi Id | MGI:6468918 | Doi | 10.1016/j.molcel.2020.04.034 |
| Citation | Wu SY, et al. (2020) Opposing Functions of BRD4 Isoforms in Breast Cancer. Mol Cell 78(6):1114-1132.e10 |
| abstractText | Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4. |
