Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis.
Transforming growth factor-beta regulator SnoN modulates mammary gland branching morphogenesis, postlactational involution, and mammary tumorigenesis.
复制标题
转化生长因子-Beta调节剂SNON调节乳腺分支形态发生，肠道术后差异和乳腺肿瘤发生。
DOI：
10.1158/0008-5472.can-10-0135
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发表时间：
2010-05-15
期刊：
影响因子：
11.2
通讯作者：
Luo K
中科院分区：
文献类型：
--
作者：
Jahchan NS;You YH;Muller WJ;Luo K
SnoN是转化生长因子-β（TGF-β）信号传导的重要负调节因子，其最初被鉴定为鸡胚胎成纤维细胞中的转化癌基因。已报道SnoN的促癌和抗癌活性，但其在正常上皮细胞中的功能尚未确定。在小鼠乳腺中，SnoN的表达水平相对较低，但在哺乳期和退化早期下调之前，在妊娠晚期短暂上调。为了评估SnoN水平升高的影响，我们产生了在小鼠乳腺肿瘤病毒启动子控制下表达SnoN片段的转基因小鼠。在该模型系统中，SnoN升高增加侧分支和小叶肺泡增殖处女腺，而加速退化泌乳后腺体。由SnoN刺激的增殖增加不足以诱导乳腺肿瘤发生。相反，SnoN水平升高与多瘤中T抗原合作，加速侵袭性多灶性腺癌的形成，并增加肺转移的形成。我们的研究定义了SnoN在乳腺上皮细胞增殖和退化中的功能，并提供了SnoN在哺乳动物肿瘤发生中的促癌作用的第一个体内证据。
SnoN is an important negative regulator of transforming growth factor-β (TGF-β) signaling that was originally identified as a transforming oncogene in chicken embryonic fibroblasts. Both pro-oncogenic and antioncogenic activities of SnoN have been reported, but its function in normal epithelial cells has not been defined. In the mouse mammary gland, SnoN is expressed at relatively low levels, but it is transiently upregulated at late gestation before being downregulated during lactation and early involution. To assess the effects of elevated levels of SnoN, we generated transgenic mice expressing a SnoN fragment under the control of the mouse mammary tumor virus promoter. In this model system, SnoN elevation increased side-branching and lobular-alveolar proliferation in virgin glands, while accelerating involution in postlactation glands. Increased proliferation stimulated by SnoN was insufficient to induce mammary tumorigenesis. In contrast, elevated levels of SnoN cooperated with polyoma middle T antigen to accelerate the formation of aggressive multifocal adenocarcinomas and to increase the formation of pulmonary metastases. Our studies define functions of SnoN in mammary epithelial cell proliferation and involution, and provide the first in vivo evidence of a pro-oncogenic role for SnoN in mammalian tumorigenesis.