Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Commun. 2017 Feb 13;8:14431. doi: 10.1038/ncomms14431.
Most breast cancers may have a luminal origin. TP53 is one of the most frequently mutated genes in breast cancers. However, how p53 deficiency contributes to breast tumorigenesis from luminal cells remains elusive. Here we report that induced p53 loss in Krt8 mammary luminal cells leads to their clonal expansion without directly affecting their luminal identity. All induced mice develop mammary tumours with 9qA1 (Yap1) and/or 6qA2 (Met) amplification(s). These tumours exhibit a mammary stem cell (MaSC)-like expression signature and most closely resemble claudin-low breast cancer. Thus, although p53 does not directly control the luminal fate, its loss facilitates acquisition of MaSC-like properties by luminal cells and predisposes them to development of mammary tumours with loss of luminal identity. Our data also suggest that claudin-low breast cancer can develop from luminal cells, possibly via a basal-like intermediate state, although further study using a different luminal promoter is needed to fully support this conclusion.
大多数乳腺癌可能起源于腔细胞。TP53 是乳腺癌中最常发生突变的基因之一。然而，p53 缺失如何促进腔细胞发生乳腺癌仍然难以捉摸。在这里，我们报告诱导 Krt8 乳腺腔细胞中的 p53 缺失会导致其克隆扩增，而不会直接影响其腔细胞特性。所有诱导的小鼠都发展出具有 9qA1（Yap1）和/或 6qA2（Met）扩增的乳腺肿瘤。这些肿瘤表现出类似于乳腺干细胞（MaSC）的表达特征，与 Claudin-low 乳腺癌最为相似。因此，尽管 p53 不能直接控制腔细胞命运，但它的缺失促进了腔细胞获得 MaSC 样特性，并使它们容易发展出失去腔细胞特征的乳腺肿瘤。我们的数据还表明，Claudin-low 乳腺癌可能起源于腔细胞，可能通过基底样中间状态，但需要使用不同的腔细胞启动子进行进一步研究，以充分支持这一结论。
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