Lane T F, Leder P
Howard Hughes Medical Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Oncogene. 1997 Oct;15(18):2133-44. doi: 10.1038/sj.onc.1201593.
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 Wnt-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 Wnt genes expressed early in mammary development, play a role in regulating sexual dimorphism and show potent transforming activity when overexpressed.
Wnt-10b在小鼠胚胎乳腺原基形成过程中表达，其表达在青春期持续，此时乳腺导管模式在卵巢类固醇的控制下建立。最近，Wnt-10b基因座的病毒激活将其过表达与乳腺肿瘤形成联系起来，表明Wnt-10b在乳腺的模式形成和生长调节中起作用。为了验证这一观点，我们构建了在MMTV启动子/增强子控制下表达高水平Wnt-10b的转基因小鼠品系。该基因的过表达导致乳腺发生深刻的发育改变，包括腺体发育扩大和处女雌性小鼠中肺泡早熟出现。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症。雄性乳腺原基中Wnt-10b的异常表达显然绕过了卵巢激素控制对刺激乳腺导管生长的正常需求以及雄激素的抑制作用。除了这些发育影响外，两性转基因小鼠都极易发生乳腺腺癌。这些肿瘤以单发方式出现，表明Wnt-10b是一种原癌基因，它为肿瘤发生提供了必要但不充分的信号。与此相关的是，尽管Fgf基因是一类常被认为在Wnt介导的肿瘤形成中起协同作用的基因，但在这些肿瘤中没有FGF mRNA扩增表达的证据。事实上，MMTV-Wnt-10b和MMTV-FGF-3/int-2的共表达导致后代不育，乳腺上皮高度紊乱，表明它们各自的发育途径之间存在强大的相互作用。这些结果表明，Wnt-10b或在乳腺发育早期表达的其他Wnt基因在调节性别二态性中起作用，并且过表达时显示出强大的转化活性。
