MUC1 alters β-catenin-dependent tumor formation and promotes cellular invasion
MUC1 alters β-catenin-dependent tumor formation and promotes cellular invasion
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DOI：
10.1038/sj.onc.1206291
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发表时间：
2003-03-06
期刊：
影响因子：
8
通讯作者：
Gendler, SJ
中科院分区：
文献类型：
--
作者：
Schroeder, JA;Adriance, MC;Gendler, SJ
MUC1 在超过 90% 的乳腺癌中异常表达，但其作为肿瘤抗原的功能尚不完全清楚。最近的研究表明，MUC1 与 β-catenin、erbB 受体、src、GSK-3beta 和蛋白激酶 Cdelta 相互作用，可能形成复合物，促进粘附连接的分解和细胞的侵袭。在这里，我们发现 MMTV-Wnt-1 转基因小鼠中 Muc1 表达的缺失导致乳腺肿瘤发病时间显着增加。在野生型 Muc1 背景上对 MMTV-Wnt-1 肿瘤的分析显示，Muc1 和 β-连环蛋白之间形成了肿瘤特异性复合物，该复合物在转化上皮的膜和细胞质中均可观察到。对原发性人类腺癌的分析表明，这种 MUC1/β-连环蛋白相互作用发生在原发性和转移性肿瘤中，但在转移性病变中显着增加。在侵袭性 MDA-MB-468 和 MDA-MB-231 细胞系中添加 MUC1 胞质结构域肽可增加其侵袭能力，并且这些肽与 β-连环蛋白和粘着斑蛋白纽蛋白共定位，主要位于膜侵入胶原基质的位点。这些数据表明MUC1通过调节β-连环蛋白定位和随后的细胞骨架动力学促进乳腺侵袭性肿瘤发生的潜在机制。
MUC1 is aberrantly expressed in greater than 90% of all breast carcinomas, yet its function as a tumor antigen is not fully understood. Recently, studies have shown that MUC1 interacts with beta-catenin, erbB receptors, src, GSK-3beta and protein kinase Cdelta, possibly in a complex that promotes the disassembly of adherens junctions and the invasion of cells. Here we show that the deletion of Muc1 expression from MMTV-Wnt-1 transgenic mice results in a significant increase in the time to mammary gland tumor onset. Analysis of MMTV-Wnt-1 tumors on a wild-type Muc1 background shows a tumor-specific complex formation between Muc1 and beta-catenin that can be observed in both the membrane and the cytoplasm of transformed epithelium. Analysis of primary human adenocarcinomas revealed that this MUC1/beta-catenin interaction occurs in both primary and metastatic tumors, but is dramatically increased in metastatic lesions. Addition of MUC1-cytoplasmic domain peptides to the invasive MDA-MB-468 and MDA-MB-231 cell lines increases their invasive capability, and these peptides colocalize with both beta-catenin and the focal adhesion protein vinculin, primarily at sites of membrane invasion into a collagen matrix. These data indicate a potential mechanism for MUC1 promotion of invasive tumorigenesis in the breast through the modulation of beta-catenin localization and subsequent cytoskeletal dynamics.