A requirement for p120-catenin in the metastasis of invasive ductal breast cancer
A requirement for p120-catenin in the metastasis of invasive ductal breast cancer
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DOI：
10.1242/jcs.250639
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发表时间：
2021-03-01
影响因子：
4
通讯作者：
Reynolds, Albert B.
中科院分区：
文献类型：
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作者：
Kurley, Sarah J.;Tischler, Verena;Reynolds, Albert B.
我们在此报告了靶向p120-连环蛋白（由CTNND 1编码;下文称为p120）敲除（KO）在侵袭性导管（乳腺）癌（IDC）PyMT小鼠模型中的作用。镶嵌p120消融对原发性肿瘤生长几乎没有影响，但在肿瘤微环境中引起显著的促转移改变，最终导致肺转移灶的数量和大小显著增加。令人惊讶的是，尽管p120消融的早期效应包括细胞间粘附力降低和侵袭力增加，但缺乏p120的细胞几乎完全无法在体内远处转移部位定植。通过分析1126个IDC的大型临床数据集，确定了该观察结果与人类IDC的相关性。正如其他人所报道的，原发性IDC中p120下调预示着更差的总生存率。然而，在小鼠中，远处转移几乎总是p120阳性，即使在原发肿瘤p120阴性的匹配病例中也是如此。总的来说，我们的研究结果证明了p120（可能还有E-cadherin）在远处转移定植过程中的积极作用。另一方面，原发性肿瘤中p120的下调通过肿瘤微环境的促转移调节间接增强了转移性播散。
We report here the effects of targeted p120-catenin (encoded by CTNND1; hereafter denoted p120) knockout (KO) in a PyMT mouse model of invasive ductal (mammary) cancer (IDC). Mosaic p120 ablation had little effect on primary tumor growth but caused significant pro-metastatic alterations in the tumor microenvironment, ultimately leading to a marked increase in the number and size of pulmonary metastases. Surprisingly, although early effects of p120-ablation included decreased cell-cell adhesion and increased invasiveness, cells lacking p120 were almost entirely unable to colonized distant metastatic sites in vivo. The relevance of this observation to human IDC was established by analysis of a large clinical dataset of 1126 IDCs. As reported by others, p120 downregulation in primary IDC predicted worse overall survival. However, as in the mice, distant metastases were almost invariably p120 positive, even in matched cases where the primary tumors were p120 negative. Collectively, our results demonstrate a strong positive role for p120 (and presumably E-cadherin) duringmetastatic colonization of distant sites. On the other hand, downregulation of p120 in the primary tumor enhanced metastatic dissemination indirectly via pro-metastatic conditioning of the tumor microenvironment.