Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.

中文翻译：

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由转录因子高阶组装驱动的增强子重编程促进表型可塑性和乳腺癌内分泌抵抗。

获得性治疗耐药是抗癌治疗的主要问题，但潜在的分子机制仍不清楚。使用已建立的乳腺癌细胞模型，我们表明内分泌抵抗与增强的表型可塑性相关，表现为管腔/上皮分化标志物的普遍下调和基底/间充质侵袭性标志物的上调。一致地，在对内分泌治疗有抗性的临床乳腺肿瘤和患者来源的异种移植样本中发现了类似的基因表达变化。从机制上讲，雌激素受体 α 和其他致癌转录因子（以 GATA3 和 AP1 为例）之间的差异相互作用驱动全局增强子增益/丢失重编程，深刻改变了乳腺癌的转录程序。我们在多种培养和异种移植模型中的功能研究揭示了 GATA3 和 AP1 在重新组织增强子景观和调节癌症表型方面的协调作用。总的来说，我们的研究表明，增强子上转录因子的不同高阶组装会触发全基因组增强子重编程，从而导致促进肿瘤表型可塑性和治疗抗性的转录转变。