Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice
Wnt-10b directs hypermorphic development and transformation in mammary glands of male and female mice
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DOI：
10.1038/sj.onc.1201593
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发表时间：
1997-10-30
期刊：
影响因子：
8
通讯作者：
Philip, L
中科院分区：
文献类型：
--
作者：
Lane, TF;Philip, L
Wnt-10b在小鼠胚胎中乳腺雏形的形成过程中表达，其表达持续到青春期，此时在卵巢类固醇的控制下建立了乳腺导管模式。最近，病毒激活的Wnt-10b位点将其过表达与乳腺肿瘤的形成联系起来，这表明Wnt-10b在乳腺的模式和生长调节中起作用。我们创建了在MMTV启动子/增强子控制下表达高水平Wnt-10b的转基因小鼠系。该基因的过度表达导致了乳腺发育的深刻改变，包括在处女雌性中腺体发育扩大和肺泡过早出现。此外，转基因雄性小鼠也表现出显著的乳腺发育，包括高度分支的乳腺导管和男性乳房发育。Wnt-10b在雄性乳腺基础中的异常表达明显绕过了卵巢激素控制刺激乳腺导管生长的正常需求和雄激素的抑制作用，除了这些发育作用外，转基因小鼠的两性都高度容易发生乳腺腺癌，这种肿瘤以孤立的方式出现，表明Wnt-10b是一种原癌基因，提供了必要的与此相关的是，没有证据表明FGF mrna在这些肿瘤中表达扩增，尽管FGF是一类经常被认为是wilt介导的肿瘤形成的合作伙伴的基因。事实上，MMTV-Wnt-10b和MMTV-FGF-3/int-2的共同表达导致不育后代具有高度紊乱的乳腺上皮，表明它们各自的发育途径之间存在有效的相互作用。或其他Wilt基因在乳腺发育早期表达，在调节两性二态性中起作用，并在过度表达时表现出强大的转化活性。
Wnt-10b is expressed during the formation of the mammary rudiment in mouse embryos and its expression continues through puberty when the mammary ductal pattern is established under control of ovarian steroids, Recently, viral activation of the Wnt-10b locus has linked its overexpression to mammary tumor formation, suggesting a role for Wnt-10b in patterning and growth-regulation of the mammary gland, To test this notion, we created lines of transgenic mice that express elevated levels of Wnt-10b under the control of the MMTV promoter/enhancer. Overexpression of this gene resulted in profound developmental alterations in the mammary gland, including expanded glandular development and the precocious appearance of alveoli in virgin females, Moreover, transgenic male mice also exhibited dramatic mammary development involving highly branched mammary ducts and gynecomastia. Aberrant expression of Wnt-10b in the mammary rudiments of males evidently bypasses the normal requirement for ovarian hormonal control in stimulating mammary ductal growth and the repressive effects of androgens, In addition to these developmental effects, transgenic mice of both sexes were highly susceptible to the development of mammary adenocarcinomas, Such tumors arose in a solitary manner indicating that Wnt-10b is a proto-oncogene which provides a necessary, but insufficient signal for oncogenesis, Relevant to this, there was no evidence of amplified expression of FGF mRNAs in these tumors though the Fgf's are a class of genes often implicated as collaborators in Wilt-mediated tumor formation, Indeed, co-expression of MMTV-Wnt-10b and MMTV-FGF-3/int-2 resulted in sterile offspring with highly disorganized mammary epithelium, demonstrating a potent interaction between their respective developmental pathways, These results suggest that Wnt-10b, or other Wilt genes expressed early in mammary development, play a role in regulating sexual dimorphism and show potent transforming activity when overexpressed.