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.

在正在进行的主要破坏BRD4调节的转录程序的临床试验中，含溴结构域的蛋白4（BRD4）是癌症的治疗靶标。BRD4在癌症中的作用主要归因于丰富的长同工型（BRD4-L）。在这里，我们通过同工型特异性敲除和内源蛋白检测以及转基因表达显示出，较不丰富的BRD4短同工型（BRD4-S）具有致癌性，而BRD4-L在乳腺癌细胞的增殖和迁移中也具​​有肿瘤抑制作用。由于乳腺肿瘤的形成和转移。通过整合的RNA序列，全基因组ChIP序列以及CUT＆RUN关联分析，我们确定Engrailed-1（EN1）同源框转录因子是关键的BRD4-S调控因子，尤其是在三阴性乳腺癌中。BRD4-S和EN1通过增强与癌症相关的基因和途径的调控，共同调节细胞外基质（ECM）相关的基质网络，包括II型胱抑素基因簇，粘蛋白5和组织蛋白酶基因座。我们的工作凸显了靶向疗法对于BRD4的致癌性（而不是肿瘤抑制性）活性的重要性。