Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells
Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells
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DOI：
10.1073/pnas.0503793102
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发表时间：
2005-06-28
影响因子：
11.1
通讯作者：
Lee, WH
中科院分区：
文献类型：
--
作者：
Furuta, S;Jiang, XZ;Lee, WH
大量证据表明，乳腺癌相关基因1（BRCA 1）参与DNA损伤修复和细胞周期检查点调控，作为肿瘤易感基因维持着整体基因组的稳定性。然而，BRCA 1是否在细胞增殖和分化中起直接作用，这是肿瘤发生中的两个关键生物学功能，目前尚不清楚。在这里，我们证明BRCA 1介导的乳腺上皮细胞（MEC）的分化腺泡形成通过使用体外三维培养系统。通过RNA干扰减少MEC中的BRCA 1损害腺泡形成，但增强增殖。这种畸变可以通过表达野生型BRCA 1以及在RAD 50-bincling结构域但不在C-末端BRCT结构域的突变体来挽救，这表明C-末端BRCT结构域在这些过程中具有关键作用。一致地，BRCA 1的缺失上调增殖基因的表达，但下调分化基因的表达。此外，通过应用分化正常MEC的条件培养基，可以逆转BRCA 1功能降低的分化缺陷型乳腺癌细胞的表型。我们的观察结果表明，BRCA 1参与了某些旁分泌/自分泌因子的分泌，这些因子诱导MEC对细胞外基质信号的反应而分化，这部分地解释了由于BRCA 1的丢失或减少而导致的散发性或家族性乳腺癌的病因学基础。
Cumulative evidence indicates that breast cancer-associated gene 1 (BRCA1) participates in DNA damage repair and cell-cycle checkpoint control, serving as a tumor susceptibility gene to maintain the global genomic stability. However, whether BRCA1 has a direct role in cell proliferation and differentiation, two key biological functions in tumorigenesis, remains unclear. Here we demonstrate BRCA1 mediates differentiation of mammary epithelial cell (MEC) for acinus formation by using the in vitro 3D culture system. Reduction of BRCA1 in MEC by RNA interference impairs the acinus formation but enhances proliferation. Such aberrations can be rescued by expression of wild-type BRCA1 as well as a mutant at the RAD50-bincling domain but not at the C-terminal BRCT domain, suggesting that the C-terminal BRCT domain has a critical role in these processes. Consistently, depletion of BRCA1 up-regulates the gene expression for proliferation but down-regulates that for differentiation. Moreover, application of the medium conditioned by differentiating normal MEC can reverse the phenotypes of differentiation-defective breast cancer cells bearing reduced BRCA1 functions. Our observation implies BRCA1 is involved in secretion of certain paracrine/autocrine factors that induce MEC differentiation in response to extracellular matrix signals, providing, in part, an explanation for the etiological basis of either sporadic or familial breast cancer due to the loss or reduction of BRCA1.