Loss of the BRCA1-interacting helicase BRIP1 results in abnormal mammary acinar morphogenesis.
Loss of the BRCA1-interacting helicase BRIP1 results in abnormal mammary acinar morphogenesis.
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DOI：
10.1371/journal.pone.0074013
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shimada Y
中科院分区：
文献类型：
--
作者：
Daino K;Imaoka T;Morioka T;Tani S;Iizuka D;Nishimura M;Shimada Y
BRIP1是一种DNA解旋酶，直接与乳腺癌易感蛋白BRCA1的C端BRCT重复序列相互作用，在BRCA1依赖的DNA修复和DNA损伤诱导的检查点控制中发挥重要作用。最近的研究表明BRIP1是一个中/低外显性乳腺癌易感基因。然而，BRIP1功能障碍的表型效应及其在乳腺癌发生中的作用仍不清楚。为了探讨BRIP1在乳腺上皮细胞腺泡形态发生中的作用，我们通过短发夹状RNA(ShRNA)介导的RNA干扰获得了BRIP1基因敲除的MCF-10A细胞，并在三维培养模型中检测了其作用。通过基因芯片和定量RT-PCR进行全基因组基因表达谱分析，以确定BRIP1基因敲除细胞与对照细胞相比基因表达的变化。使用通路分析和基因集浓缩分析(GSEA)进一步研究微阵列数据以鉴定通路。在非恶性的MCF-10A乳腺上皮细胞中，通过RNA干扰将BRIP1基因敲除，可引起肿瘤样改变，如异常细胞黏附、细胞增殖增加、大而不规则的腺泡、侵袭性生长和缺陷的腔形成。在BRIP1基因敲除的细胞中，差异表达的基因包括MCAM、COL8A1、WIPF1、RICH2、PCSK5、GAS1、SATB1和ELF3，与对照细胞相比，差异表达基因分为几个功能组，如细胞黏附、极性、生长、信号转导和发育过程。信号通路分析表明，BRIP1基因敲除细胞中LPA受体、Myc、Wnt、PI3K、PTEN以及DNA损伤反应等多种细胞信号通路异常。因此，BRIP1的缺失扰乱了正常的乳腺形态发生，并导致肿瘤样变化，可能是通过功能失调的多个细胞信号通路在乳腺的正常发育中发挥作用。
BRIP1 is a DNA helicase that directly interacts with the C-terminal BRCT repeat of the breast cancer susceptibility protein BRCA1 and plays an important role in BRCA1-dependent DNA repair and DNA damage–induced checkpoint control. Recent studies implicate BRIP1 as a moderate/low-penetrance breast cancer susceptibility gene. However, the phenotypic effects of BRIP1 dysfunction and its role in breast cancer tumorigenesis remain unclear. To explore the function of BRIP1 in acinar morphogenesis of mammary epithelial cells, we generated BRIP1-knockdown MCF-10A cells by short hairpin RNA (shRNA)-mediated RNA interference and examined its effect in a three-dimensional culture model. Genome-wide gene expression profiling by microarray and quantitative RT-PCR were performed to identify alterations in gene expression in BRIP1-knockdown cells compared with control cells. The microarray data were further investigated using the pathway analysis and Gene Set Enrichment Analysis (GSEA) for pathway identification. BRIP1 knockdown in non-malignant MCF-10A mammary epithelial cells by RNA interference induced neoplastic-like changes such as abnormal cell adhesion, increased cell proliferation, large and irregular-shaped acini, invasive growth, and defective lumen formation. Differentially expressed genes, including MCAM, COL8A1, WIPF1, RICH2, PCSK5, GAS1, SATB1, and ELF3, in BRIP1-knockdown cells compared with control cells were categorized into several functional groups, such as cell adhesion, polarity, growth, signal transduction, and developmental process. Signaling-pathway analyses showed dysregulation of multiple cellular signaling pathways, involving LPA receptor, Myc, Wnt, PI3K, PTEN as well as DNA damage response, in BRIP1-knockdown cells. Loss of BRIP1 thus disrupts normal mammary morphogenesis and causes neoplastic-like changes, possibly via dysregulating multiple cellular signaling pathways functioning in the normal development of mammary glands.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
极性和增殖受到乳腺上皮肿瘤细胞下游的不同信号通路的控制。
影响因子：
7.8
作者：
Liu, Hong;Radisky, Derek C;Wang, Fei;Bissell, Mina J
通讯作者：
Bissell, Mina J
影响因子：
12.3
作者：
Kurisu S;Takenawa T
通讯作者：
Takenawa T
影响因子：
11.2
作者：
Fournier MV;Fata JE;Martin KJ;Yaswen P;Bissell MJ
通讯作者：
Bissell MJ
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS