Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk. Refer to individual Series

在与BRCA1突变相关的乳腺癌中，管腔祖细胞（luminal progenitor cells）被认为是肿瘤起源细胞，但此类细胞如何转变为侵袭性癌细胞的机制仍不甚明晰。本研究结合单细胞表观基因组学（single-cell epigenomics）与转录组学（transcriptomics）数据，重构了管腔细胞中驱动肿瘤发生的事件时序。当敲除Trp53与Brca1基因后，研究发现管腔祖细胞出现广泛的表观基因组紊乱，并伴随细胞身份丧失。此类细胞随后通过Snail介导的部分上皮间质转化（partial epithelial-to-mesenchymal transition），以及与肿瘤微环境协同的免疫抑制信号与成纤维细胞生长因子（fibroblast growth factor, FGF）信号的适时激活，进展为肿瘤。在人类样本中，可在复发率极低的早期基底样肿瘤，以及罹患癌症的BRCA1突变携带者的正常样乳腺组织中检测到瘤前改变。本研究填补了我们对BRCA1驱动的肿瘤发生机制认知中的关键空白，为高癌症风险人群的早期监测提供了全新视角。请参阅各独立数据集系列