识别控制癌细胞增殖和存活的主要表观遗传因素可以发现新的分子靶标，可用于克服对当前药物治疗方案的耐药性。在乳腺癌 (BC) 中，对内分泌治疗 (ET) 的抵抗是由于遗传和表观遗传事件导致的异常雌激素受体 α (ERα) 信号传导引起的，目前仍主要未知。靶向 ERα 通路的关键上游成分提供了一种独立于任何其他下游事件干扰癌细胞中雌激素信号传导的方法。通过将全基因组“脱落”筛选的计算分析与 siRNA 介导的基因敲低 (kd) 相结合，我们在类腔 ERα  BC 中鉴定了一组必需基因，其中包括 BRPF1，编码含溴结构域的蛋白质属于表观遗传阅读器家族，充当染色质重塑者来控制基因转录。为了深入了解 BRPF1 在 BC 和 ERα 信号传导中的作用，我们应用了染色质和转录组分析、基因消融和靶向药理学抑制以及细胞和功能测定。结果表明，BRPF1 与 BC 细胞染色质上的 ERα 结合，其阻断可抑制细胞周期进展、减少细胞增殖并通过调节染色质可及性介导转录组变化。这种效应是由抗雌激素 (AE) 敏感和耐药的 BC 细胞和临床前患者衍生模型 (PDO) 中 ERα 基因沉默导致的雌激素信号传导广泛抑制引起的。 BRPF1 与 ERα 功能相互作用的表征揭示了雌激素反应性 BC 细胞存活的新调节因子，并表明该表观遗传因子是治疗这些肿瘤的潜在新靶标。© 2024。作者。

Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide 'drop-out' screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.© 2024. The Author(s).