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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >BRCA1 regulates human mammary stem/progenitor cell fate
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BRCA1 regulates human mammary stem/progenitor cell fate

机译：BRCA1调节人类乳腺干/祖细胞的命运

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Although it is well established that women with germ-line mutations in the BRCA1 gene have a greatly increased lifetime incidence of breast and ovarian cancer, the molecular mechanisms responsible for this tissue-specific carcinogenesis remain undefined. The majority of these breast cancers are of the basal-like phenotype characterized by lack of expression of ER, PR, and ERBB2. Because this phenotype has been proposed to resemble that of normal breast stem cells, we examined the role of BRCA1 in human mammary stem cell fate. Using both in vitro systems and a humanized NOD/SCID mouse model, we demonstrate that BRCA1 expression is required for the differentiation of ER-negative stem/ progenitor cells to ER-positive luminal cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells displaying the stem/progenitor cell marker ALDH1 and a decrease in cells expressing luminal epithelial markers and estrogen receptor. In breast tissues from women with germ-line BRCA1 mutations, but not normal controls, we detect entire lobules that, although histologically normal, are positive for ALDH1 expression but are negative for the expression of ER. Loss of heterozygosity for BRCA1 was documented in these ALDH1-positive lobules but not in adjacent ALDH1-negative lobules. Taken together, these studies demonstrate that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Because BRCA1 also plays a role in DNA repair, our work suggests that loss of BRCA1 may result in the accumulation of genetically unstable breast stem cells, providing prime targets for further carcinogenic events.
机译：尽管众所周知，在BRCA1基因中具有生殖系突变的女性，其一生中乳腺癌和卵巢癌的发病率大大增加，但导致这种组织特异性致癌作用的分子机制仍然不确定。这些乳腺癌中的大多数具有基底样表型，其特征在于缺乏ER，PR和ERBB2的表达。因为有人提出该表型与正常的乳腺干细胞类似，所以我们研究了BRCA1在人类乳腺干细胞命运中的作用。使用体外系统和人性化的NOD / SCID小鼠模型，我们证明BRCA1表达是将ER阴性干/祖细胞分化为ER阳性腔细胞所必需的。在原代乳腺上皮细胞中敲低BRCA1会导致显示干/祖细胞标记ALDH1的细胞增加，并导致表达腔上皮标记和雌激素受体的细胞减少。在具有生殖系BRCA1突变但非正常对照的女性的乳腺组织中，我们检测到整个小叶，尽管组织学正常，但对ALDH1表达呈阳性，但对ER表达呈阴性。在这些ALDH1阳性小叶中记录了BRCA1杂合性的丧失，但在相邻的ALDH1阴性小叶中则没有。综上所述，这些研究表明BRCA1在ER阴性干/祖细胞向ER阳性腔细胞的分化中起关键作用。由于BRCA1在DNA修复中也起作用，因此我们的研究表明，BRCA1的缺失可能导致遗传上不稳定的乳房干细胞的积累，从而为进一步的致癌事件提供了主要靶点。

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