Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice
Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice
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DOI：
10.1242/dev.00820
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发表时间：
2003-12-01
期刊：
影响因子：
4.6
通讯作者：
Deng, CX
中科院分区：
文献类型：
--
作者：
Li, WM;Qiao, WH;Deng, CX
Smad 4是TGF β信号的中心介导物，其在许多生物过程中发挥重要作用。为了研究Smad 4在乳腺发育和肿瘤形成中的作用，我们使用Cre-loxP方法破坏了乳腺上皮中的该基因。Smad 4在整个发育过程中在乳腺中表达;然而，在前三次妊娠期间，其失活并没有引起腺体的异常发育。相反，Smad 4的缺乏逐渐诱导细胞增殖，肺泡增生和乳腺上皮细胞转分化为鳞状上皮细胞。因此，所有突变小鼠在5至16月龄之间发生鳞状细胞癌和/或乳腺癌。我们证明，Smad 4的缺乏导致β-连环蛋白在发病时和整个转分化过程中的积累，暗示β-连环蛋白，Writ信号通路的关键组成部分，在Smad 4缺失乳腺鳞状上皮化生的发展。我们进一步证明，TGF β 1治疗降解β-连环蛋白，并诱导培养的乳腺上皮细胞的上皮间质转化。然而，这种行为在Smad 4缺失的情况下被阻止。这些发现表明，TGF β/Smad 4信号在乳腺发育和肿瘤形成期间的细胞命运维持中发挥作用。
Smad4 is a central mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in mammary gland development and neoplasia, we disrupted this gene in mammary epithelium using a Cre-loxP approach. Smad4 is expressed in the mammary gland throughout development; however, its inactivation did not cause abnormal development of the gland during the first three pregnancies. Instead, lack of Smad4 gradually induced cell proliferation, alveolar hyperplasia and transdifferentiation of mammary epithelial cells into squamous epithelial cells. Consequently, all mutant mice developed squamous cell carcinoma and/or mammary abscesses between 5 and 16 months of age. We demonstrated that absence of Smad4 resulted in beta-catenin accumulation at onset and throughout the process of transdifferentiation, implicating beta-catenin, a key component of the Writ signaling pathway, in the development of squamous metaplasia in Smad4-null mammary glands. We further demonstrated that TGFbeta1 treatment degraded beta-catenin and induced epithelial-mesenchymal transformation in cultured mammary epithelial cells. However, such actions were blocked in the absence of Smad4. These findings indicate that TGFbeta/Smad4 signals play a role in cell fate maintenance during mammary gland development and neoplasia.