对内分泌治疗 (ET) 的耐药性在雌激素受体 (ER) 阳性乳腺癌中很常见，大多数复发患者死于 ET 耐药性疾病。虽然基因突变为某些复发提供了解释，但在许多情况下，耐药机制仍不清楚。药物诱导的表观遗传重编程已被证明提供了可能的耐药途径。通过分析 ET 抗性模型中的组蛋白 H3 赖氨酸 27 乙酰化 (H3K27ac) 谱和转录重编程，我们发现选择性 ER 降解剂 (SERD)，例如氟维司群，可促进 VGLL1（TEAD 转录因子的共激活剂）的表达。 VGLL1 通过 TEAD 发挥作用，促进驱动氟维司群耐药乳腺癌细胞生长的基因表达。 VGLL1/TEAD4 相互作用的药理破坏抑制了 VGLL1/TEAD 诱导的转录程序，从而防止耐药细胞的生长。 EGFR 是 VGLL1/TEAD 调节的基因之一，VGLL1 引导的 EGFR 上调使氟维司群耐药乳腺癌细胞对 EGFR 抑制剂敏感。总而言之，这些发现确定 VGLL1 是 ET 耐药性的转录驱动因素，并为复发性 ER 乳腺癌患者提供了治疗的可能性。

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer, and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapses, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming has been shown to provide possible routes to resistance. By analyzing histone H3 lysine 27 acetylation (H3K27ac) profiles and transcriptional reprogramming in models of ET resistance, we discovered that selective ER degraders (SERDs), such as fulvestrant, promote expression of VGLL1, a co-activator for TEAD transcription factors. VGLL1, acting via TEADs, promoted expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibited VGLL1/TEAD-induced transcriptional programs to prevent growth of resistant cells. EGFR was among the VGLL1/TEAD-regulated genes, and VGLL1-directed EGFR upregulation sensitized fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, these findings identify VGLL1 as a transcriptional driver in ET resistance and advance therapeutic possibilities for relapsed ER+ breast cancer patients.