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.

种系 BRCA1 突变携带者面临较高的乳腺癌风险;然而，这种风险的潜在机制尚不完全清楚。使用种系 Brca1 杂合性的新基因工程小鼠模型，我们证明了 Brca1 杂合背景中的早期肿瘤发作不能完全用传统的“二击”假说来解释，这表明 Brca1 杂合状态中存在固有的促进肿瘤的改变。通过测序分析对转座酶可及染色质进行单细胞 RNA 测序和检测，在表面上正常的 Brca1 杂合乳腺上皮细胞中发现了一组独特的差异可及染色质区域，与野生型细胞不同，部分模拟肿瘤细胞中的染色质和 RNA 水平变化。转录因子分析确定了这些表观遗传引发区域中 ELF5 的缺失和 AP-1 位点的增加;体内实验进一步表明 AP-1 和 Wnt10a 是 Brca1 相关乳腺癌的强启动子。这些发现揭示了 Brca1 单倍体不足在加速肿瘤发生、推进我们的机制理解和为潜在的治疗策略提供信息方面以前未被重视的表观遗传效应。