美国哈佛医学院Joan S. Brugge等研究人员合作发现，Brca1基因半显性不足促进遗传性乳腺癌小鼠模型中，肿瘤早期发生和表观遗传改变。相关论文于2024年11月11日在线发表在《自然—遗传学》杂志上。

通过使用一种新的基因工程小鼠模型研究种系Brca1杂合缺失的效应，研究人员发现Brca1杂合缺失背景下的早期肿瘤发生无法完全通过传统的“二次打击”假说解释。这提示Brca1杂合状态下可能存在内在的肿瘤促进性改变。

单细胞RNA测序和转座酶可及性染色质测序分析，揭示了在表面正常的Brca1杂合乳腺上皮细胞中，存在一组独特的差异性可及性染色质区域，这些区域与野生型细胞不同，并部分模仿肿瘤细胞中的染色质和RNA水平变化。

转录因子分析发现，在这些表观遗传学上已经被激活的区域中，ELF5丧失和AP-1位点的获得。体内实验进一步表明AP-1和Wnt10a是Brca1相关乳腺癌的强效促进因子。

这些发现揭示了Brca1半显性不足在加速肿瘤发生中的表观遗传学效应，推动了人们对其机制的理解，并为潜在的治疗策略提供了新的见解。

据悉，携带BRCA1种系突变的个体面临较高的乳腺癌风险，但这种风险的潜在机制尚不完全明了。

附：英文原文

Title: Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer

Author: Li, Carman Man-Chung, Cordes, Alyssa, Oliphant, Michael U. J., Quinn, S. Aidan, Thomas, Mayura, Selfors, Laura M., Silvestri, Francesca, Girnius, Nomeda, Rinaldi, Gianmarco, Zoeller, Jason J., Shapiro, Hana, Tsiobikas, Christina, Gupta, Kushali P., Pathania, Shailja, Regev, Aviv, Kadoch, S. Cigall, Muthuswamy, Senthil K., Brugge, Joan S.

Issue&Volume: 2024-11-11

Abstract: Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional ‘two-hit’ hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.

DOI: 10.1038/s41588-024-01958-6

Source: https://www.nature.com/articles/s41588-024-01958-6