Replacement of E-cadherin by N-cadherin in the mammary gland leads to fibrocystic changes and tumor formation.
Replacement of E-cadherin by N-cadherin in the mammary gland leads to fibrocystic changes and tumor formation.
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DOI：
10.1186/bcr3046
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发表时间：
2011-10-26
期刊：
影响因子：
--
通讯作者：
Kemler R
中科院分区：
文献类型：
--
作者：
Kotb AM;Hierholzer A;Kemler R
E-cadherin （E-cad; cadherin 1）和N-cadherin （N-cad; cadherin 2）是细胞粘附分子cadherin家族中最重要的成员。尽管它们具有许多共同的结构和功能特征，但它们在体内的表达方式几乎是相互排斥的。为了探索两种钙粘蛋白在体内的功能差异，我们最近创建了一个敲入系，其中N-cad是从E-cad位点表达的。结合条件基因失活方法，我们在妊娠后期开始的乳腺肺泡上皮细胞中表达了N-cad在E-cad缺失的情况下（称为ncadk - i）。我们发现，N-cad的单独存在可诱导构成活性的成纤维细胞生长因子（Fgf）信号传导和早衰，导致肺泡细胞大量凋亡。为了阻断细胞凋亡，我们有条件地删除了ncadk细胞中p53的一个等位基因。并观察到肺泡形态和功能在时间上的恢复。然而，随着年龄和哺乳周期的增加，观察到纤维化组织和囊肿的积累。这种表型与纤维囊性乳房病（FM）非常相似，FM是一种常见的人类疾病，被认为是乳腺癌的前兆。同样，55%的ncadk。携带p53杂合缺失的小鼠发展为恶性和侵袭性肿瘤。我们的研究结果证明了N-cad在乳腺纤维化和囊肿形成中的可能作用。此外，我们表明这些病变先于恶性肿瘤的发展。因此，我们提供了一种新的小鼠模型来研究纤维囊性乳腺病变的分子机制以及良性肿瘤向恶性肿瘤的转变。
E-cadherin (E-cad; cadherin 1) and N-cadherin (N-cad; cadherin 2) are the most prominent members of the cadherin family of cell adhesion molecules. Although they share many structural and functional features, they are expressed in an almost mutually exclusive manner in vivo. To explore functional differences between the two cadherins in vivo, we recently generated a knock-in line in which N-cad is expressed from the E-cad locus. In combination with a conditional gene inactivation approach, we expressed N-cad in the absence of E-cad (referred to as Ncadk.i.) in alveolar epithelial cells of the mammary gland starting in late pregnancy. We found that the sole presence of N-cad induces constitutively active fibroblast growth factor (Fgf) signaling and a precocious involution resulting in massive apoptosis of alveolar cells. To block apoptosis, we conditionally deleted one allele of p53 in Ncadk.i. mice and observed a temporal rescue of alveolar morphology and function. However, an accumulation of fibrotic tissue and cysts with increasing age and lactation cycles was observed. This phenotype closely resembled fibrocystic mastopathy (FM), a common disorder in humans, which is thought to precede breast cancer. Concordantly, 55% of Ncadk.i. mice harboring a heterozygous p53 deletion developed malignant and invasive tumors. Our results demonstrate a possible role for N-cad in the formation of fibrosis and cysts in the mammary gland. Moreover, we show that these lesions precede the development of malignant tumors. Thus, we provide a new mouse model to investigate the molecular mechanisms of fibrocystic mastopathy and the transition from benign to malignant tumors.
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影响因子：
4.6
作者：
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作者：
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