三阴性乳腺癌（TNBC）是临床上具有侵袭性的乳腺癌亚型。核心转录调节电路 (CRC) 由自动调节转录因子 (TF) 及其增强子组成，它们主导基因表达程序并控制细胞命运。然而，TNBC 对 CRC 的了解有限。在此，我们系统地表征了乳腺癌中激活的超级增强子 (SE) 并研究了 14 个 CRC。我们发现CRC可能广泛参与DNA构象变化、代谢过程和影响基因表达重编程的信号反应。此外，这些 CRC TF 能够与桥接增强子-启动子环的伙伴 TF 协调。值得注意的是，CRC TF 和伙伴对对乳腺癌分子亚型（尤其是 TNBC）表现出显着的特异性。 USF1、SOX4 和 MYBL2 被确定为 TNBC 特异性 CRC TF。我们进一步证明 USF1 是 TNBC 免疫表型相关的 TF。我们发现增强子驱动的 CRC 重新布线与癌症免疫和死亡率相关，这将有助于表观遗传抗癌治疗策略的发展。版权所有 © 2023 Shi、Zhong、Dong、Hu 和 Li。

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer. Core transcriptional regulatory circuitry (CRC) consists of autoregulated transcription factors (TFs) and their enhancers, which dominate gene expression programs and control cell fate. However, there is limited knowledge of CRC in TNBC. Herein, we systemically characterized the activated super-enhancers (SEs) and interrogated 14 CRCs in breast cancer. We found that CRCs could be broadly involved in DNA conformation change, metabolism process, and signaling response affecting the gene expression reprogramming. Furthermore, these CRC TFs are capable of coordinating with partner TFs bridging the enhancer-promoter loops. Notably, the CRC TF and partner pairs show remarkable specificity for molecular subtypes of breast cancer, especially in TNBC. USF1, SOX4, and MYBL2 were identified as the TNBC-specific CRC TFs. We further demonstrated that USF1 was a TNBC immunophenotype-related TF. Our findings that the rewiring of enhancer-driven CRCs was related to cancer immune and mortality, will facilitate the development of epigenetic anti-cancer treatment strategies.Copyright © 2023 Shi, Zhong, Dong, Hu and Li.