BRCA1 regulates human mammary stem/progenitor cell fate
BRCA1 regulates human mammary stem/progenitor cell fate
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DOI：
10.1073/pnas.0711613105
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发表时间：
2008-02-05
影响因子：
11.1
通讯作者：
Wicha, Max S.
中科院分区：
文献类型：
--
作者：
Liu, Suling;Ginestier, Christophe;Wicha, Max S.
尽管BRCA 1基因发生生殖系突变的女性乳腺癌和卵巢癌的终生发病率大大增加，但这种组织特异性致癌作用的分子机制仍不明确。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ERBB 2的表达。由于这种表型被认为与正常乳腺干细胞相似，我们研究了BRCA 1在人类乳腺干细胞命运中的作用。使用体外系统和人源化NOD/SCID小鼠模型，我们证明BRCA 1表达是ER阴性干/祖细胞分化为ER阳性管腔细胞所必需的。原代乳腺上皮细胞中BRCA 1的敲低导致展示干/祖细胞标志物ALDH 1的细胞增加，表达管腔上皮标志物和雌激素受体的细胞减少。在生殖系BRCA 1突变的女性乳腺组织中，但不是正常对照，我们检测到整个小叶，虽然组织学正常，但ALDH 1表达阳性，但ER表达阴性。BRCA 1杂合性丢失记录在这些ALDH 1阳性小叶，但在相邻的ALDH 1阴性小叶。总之，这些研究表明，BRCA 1在ER阴性干/祖细胞分化为ER阳性管腔细胞中起着关键作用。由于BRCA 1也在DNA修复中发挥作用，我们的工作表明BRCA 1的缺失可能导致遗传不稳定的乳腺干细胞的积累，为进一步的致癌事件提供了主要目标。
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.