The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Cell Stem Cell. 2010 Sep 3;7(3):403-17. doi: 10.1016/j.stem.2010.07.010.
Breast cancers in BRCA1 mutation carriers frequently have a distinctive basal-like phenotype. It has been suggested that this results from an origin in basal breast epithelial stem cells. Here, we demonstrate that deleting Brca1 in mouse mammary epithelial luminal progenitors produces tumors that phenocopy human BRCA1 breast cancers. They also resemble the majority of sporadic basal-like breast tumors. However, directing Brca1 deficiency to basal cells generates tumors that express molecular markers of basal breast cancers but do not histologically resemble either human BRCA1 or the majority of sporadic basal-like breast tumors. These findings support a derivation of the majority of human BRCA1-associated and sporadic basal-like tumors from luminal progenitors rather than from basal stem cells. They also demonstrate that when target cells for transformation have the potential for phenotypic plasticity, tumor phenotypes may not directly reflect histogenesis. This has important implications for cancer prevention strategies.
BRCA1 基因突变携带者的乳腺癌通常具有独特的基底样表型。有人认为这是源于基底乳腺上皮干细胞的起源。在这里,我们证明在小鼠乳腺上皮腔前体细胞中删除 Brca1 会产生类似于人类 BRCA1 乳腺癌的肿瘤。它们也类似于大多数散发性基底样乳腺癌。然而,将 Brca1 缺陷导向基底细胞会产生表达基底乳腺癌分子标志物的肿瘤,但在组织学上既不像人类 BRCA1 也不像大多数散发性基底样乳腺癌。这些发现支持大多数人类 BRCA1 相关和散发性基底样肿瘤源自腔前体细胞,而不是源自基底干细胞。它们还表明,当转化的靶细胞具有表型可塑性的潜力时,肿瘤表型可能不会直接反映组织发生。这对癌症预防策略具有重要意义。