Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Equipe Labellisée Ligue contre le Cancer, 69008, Lyon, France.
LabEx DEVweCAN, Université de Lyon, F-69000, Lyon, France.
Nat Commun. 2020 Jul 9;11(1):3431. doi: 10.1038/s41467-020-17249-7.
Claudin-low breast cancers are aggressive tumors defined by the low expression of key components of cellular junctions, associated with mesenchymal and stemness features. Although they are generally considered as the most primitive breast malignancies, their histogenesis remains elusive. Here we show that this molecular subtype of breast cancers exhibits a significant diversity, comprising three main subgroups that emerge from unique evolutionary processes. Genetic, gene methylation and gene expression analyses reveal that two of the subgroups relate, respectively, to luminal breast cancers and basal-like breast cancers through the activation of an EMT process over the course of tumor progression. The third subgroup is closely related to normal human mammary stem cells. This unique subgroup of breast cancers shows a paucity of genomic aberrations and a low frequency of TP53 mutations, supporting the emerging notion that the intrinsic properties of the cell-of-origin constitute a major determinant of the genetic history of tumorigenesis.
Claudin-low 型乳腺癌是一种侵袭性肿瘤，其特征是细胞连接的关键成分表达降低，与间充质和干细胞特征相关。尽管它们通常被认为是最原始的乳腺癌，但它们的发生机制仍不清楚。在这里，我们表明这种乳腺癌的分子亚型表现出显著的多样性，包括三个主要亚组，这些亚组是通过肿瘤进展过程中 EMT 过程的激活而从独特的进化过程中出现的。遗传、基因甲基化和基因表达分析表明，两个亚组分别与 luminal 型乳腺癌和基底样乳腺癌相关，通过 EMT 过程的激活。第三个亚组与正常的人类乳腺干细胞密切相关。这种独特的乳腺癌亚组显示出较少的基因组异常和较低的 TP53 突变频率，这支持了一个新兴的观点，即细胞起源的内在特性是肿瘤发生遗传史的主要决定因素。
