Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.
Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.
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DOI：
10.1016/j.cell.2008.09.045
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发表时间：
2008-11-28
期刊：
影响因子：
64.5
通讯作者：
Muthuswamy SK
中科院分区：
文献类型：
--
作者：
Zhan L;Rosenberg A;Bergami KC;Yu M;Xuan Z;Jaffe AB;Allred C;Muthuswamy SK
细胞极性蛋白的丧失，如Scribble，通过促进不受控制的增殖诱导果蝇中的肿瘤形成。极性蛋白在哺乳动物肿瘤发生中的作用知之甚少。我们证明，敲低乳腺上皮细胞中的Scribble会破坏细胞极性，阻断三维形态发生，抑制细胞凋亡，并诱导体内发育异常，在长时间潜伏期后进展为肿瘤。Scribble的敲除还与诸如Myc的癌基因协作以转化3D腺泡中的上皮细胞，并通过阻断细胞凋亡途径的激活在体内诱导肿瘤。与敲除一样，Scribble从细胞-细胞连接处的错误定位足以促进细胞转化。有趣的是，小鼠和人类的自发性乳腺肿瘤具有下调和错误定位的Scribble，这表明Scribble失活的选择压力。因此，我们证明，涂鸦是一种新的乳腺癌的调节和极性途径的失调促进发育不良和肿瘤生长的哺乳动物通过破坏形态发生和抑制细胞死亡。
Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation. The role polarity proteins play during tumorigenesis in mammals is poorly understood. We demonstrate that knockdown of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis and induces dysplasia in vivo that progress to tumors after long latency. Knockdown of Scribble also cooperates with oncogenes such as Myc to transform epithelial cells in 3D acini and induce tumors in vivo by blocking activation of an apoptosis pathway. Like knockdown, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation. Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble suggesting a selection-pressure for Scribble inactivation. Thus, we demonstrate that Scribble is a novel regulator of breast cancer and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
56.9
作者：
BLACKWELL, TK;KRETZNER, L;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
影响因子：
9.2
作者：
Audebert, S;Navarro, C;Borg, JP
通讯作者：
Borg, JP
影响因子：
8.8
作者：
Deming SL;Nass SJ;Dickson RB;Trock BJ
通讯作者：
Trock BJ