Activation of β-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias
Activation of β-catenin signaling in differentiated mammary secretory cells induces transdifferentiation into epidermis and squamous metaplasias
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DOI：
10.1073/pnas.012414099
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发表时间：
2002-01-08
影响因子：
11.1
通讯作者：
Khazaie, K
中科院分区：
文献类型：
--
作者：
Miyoshi, K;Shillingford, JM;Khazaie, K
乳腺原基在胚胎中形成为表皮的衍生物，这一过程由Lef-1控制，因此可能由β-连环蛋白控制。为了研究β-连环蛋白信号在乳腺肺泡上皮中的作用，我们通过缺失β-连环蛋白基因的外显子3（氨基酸5-80）来稳定内源性β-连环蛋白在分化肺泡上皮中的作用。这项任务是在携带floxed β-连环蛋白基因和Cre转基因的小鼠中完成的，Cre转基因受乳腺特异性乳清酸性蛋白（WAP）基因启动子或小鼠乳腺肿瘤病毒长末端重复序列（MMTV-LTR）的控制。稳定的β-连环蛋白是在第一次怀孕期间获得的，它的存在导致肺泡上皮细胞的去分化，然后转分化为表皮和皮拉尔结构。广泛的鳞状上皮化生，但没有腺癌，在怀孕期间β-连环蛋白激活后发展，并持续整个退化。这些数据表明β-连环蛋白信号传导的激活诱导导致乳腺上皮细胞分化丧失和表皮结构诱导的程序。
Mammary anlagen are formed in the embryo as a derivative of the epidermis, a process that is controlled by Lef-1 and therefore possibly by beta-catenin. To investigate the role of beta-catenin signaling in mammary alveolar epithelium, we have stabilized endogenous beta-catenin in differentiating alveolar epithelium through the deletion of exon 3 (amino acids 5-80) of the beta-catenin gene. This task was accomplished in mice carrying a floxed beta-catenin gene and a Cre transgene under control of the mammary-specific whey acidic protein (WAP) gene promoter or the mouse mammary tumor virus-long terminal repeat (MMTV-LTR). Stabilized beta-catenin was obtained during the first pregnancy, and its presence resulted in the dedifferentiation of alveolar epithelium followed by a transdifferentiation into epidermal and pilar structures. Extensive squamous metaplasia, but no adenocarcinomas, developed upon beta-catenin activation during pregnancy and persisted throughout involution. These data demonstrate that the activation of beta-catenin signaling induces a program that results in loss of mammary epithelial cell differentiation and induction of epidermal structures.