乳腺癌内分泌治疗获得性耐药原来如此获得性耐药又称继发性耐药、适应性耐药、逃逸性耐药，是乳腺癌内分泌治疗的主要难题，其潜在的分子机制尚不明确。
2020年5月18日，英国《自然》旗下《细胞生物学》在线发表美国德克萨斯大学毕明君、张钊、刘志杰、陈丽珍、贝勒医学院、加利福尼亚大学、法国巴黎文理研究大学居里学院、复旦大学附属肿瘤医院江一舟、龚悦、邵志敏等学者的研究报告，探讨了乳腺癌内分泌治疗获得性耐药的分子机制。
该研究利用现有的乳腺癌细胞模型，证实内分泌治疗耐药与表现型可塑性增强密切相关：•管腔样或上皮样（表现为激素受体阳性）分化基因表达减少•基底样或间质样（大多数表现为三阴性）浸润基因表达增加同样，对于临床乳腺肿瘤和内分泌治疗耐药患者来源异种移植肿瘤，发现相似的基因表达变化。
根据机制分析，雌激素受体α与GATA3和AP1等其他致癌转录因子对分化的相互作用，可以促进全基因组转录增强子重编程，获得或失去其分化前的功能，从而显著改变了乳腺癌的转录程序。
根据功能分析，通过多种乳腺癌细胞培养物和异种移植模型，证实了GATA3和AP1对于重组转录增强子染色质分布和调节乳腺癌表现型的协调作用。
因此，该研究结果表明，转录因子分化高级结构装配可以触发全基因组转录增强子重编程，从而引起基因转录发生转换，促进乳腺肿瘤表现型可塑性增强和内分泌治疗耐药。
其中，GATA3和AP1有望成为逆转乳腺癌内分泌治疗获得性耐药的潜在靶点。
Nat Cell Biol. 2020 May 18. [Epub ahead of print]Enhancer reprogramming driven by high-order assemblies of transcription factors promotes phenotypic plasticity and breast cancer endocrine resistance.Mingjun Bi, Zhao Zhang, Yi-Zhou Jiang, Pengya Xue, Hu Wang, Zhao Lai, Xiaoyong Fu, Carmine De Angelis, Yue Gong, Zhen Gao, Jianhua Ruan, Victor X. Jin, Elisabetta Marangoni, Elodie Montaudon, Christopher K. Glass, Wei Li, Tim Hui-Ming Huang, Zhi-Ming Shao, Rachel Schiff, Lizhen Chen, Zhijie Liu.University of Texas Health Science Center at San Antonio, SanAntonio, TX, USA; Fudan University Shanghai Cancer Center, Shanghai, China; Baylor College of Medicine, Houston, TX, USA; University of Texas at San Antonio, San Antonio, TX, USA; Institut Curie, PSL University, Paris, France; University of California at San Diego, La Jolla, CA, USA; University of California, Irvine, Irvine, CA, USA.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.DOI: 10.1038/s41556-020-0514-z。
