TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase.
TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase.
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DOI：
10.1158/0008-5472.can-13-0967
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发表时间：
2013-11-01
期刊：
影响因子：
11.2
通讯作者：
Ueno NT
中科院分区：
文献类型：
--
作者：
Wang X;Saso H;Iwamoto T;Xia W;Gong Y;Pusztai L;Woodward WA;Reuben JM;Warner SL;Bearss DJ;Hortobagyi GN;Hung MC;Ueno NT
炎症性乳腺癌(IBC)是最致命的乳腺癌，但其侵袭性的基础还不完全清楚。在这项研究中，我们报告了一种功能不明的膜蛋白TIG1(RARRES1)在肿瘤中的高表达可以缩短IBC患者的生存期。TIG1缺失抑制了IBC细胞的体外增殖、迁移和侵袭，并抑制了IBC细胞在体内的生长。我们鉴定了受体酪氨酸激酶Ax1是一种TIG1结合蛋白。TIG1相互作用通过抑制AXL蛋白酶体依赖的降解而使其稳定。缺失TIG1的IBC细胞AX1表达降低，NF-κB失活，MMP9表达下调，提示TIG1通过支持AXL信号通路调节IBC细胞的侵袭能力。与这些结果一致的是，用Axl抑制剂SGI-7079处理IBC细胞在体外降低了它们的恶性特性。最后，在原代人类IBC标本中，TIG1的表达与Ax1的表达呈正相关。我们的发现表明，TIG1通过支持Ax1的功能，促进对其发展的理解，并使TIG1和Ax1成为IBC治疗的有希望的治疗靶点，从而积极地改变IBC的恶性特性。
Inflammatory breast cancer (IBC) is the most lethal form of breast cancer, but the basis for its aggressive properties are not fully understood. In this study, we report that high tumoral expression of TIG1 (RARRES1), a functionally undefined membrane protein, confers shorter survival in IBC patients. TIG1 depletion decreased IBC cell proliferation, migration and invasion in vitro and inhibited tumor growth of IBC cells in vivo. We identified the receptor tyrosine kinase Axl as a TIG1 binding protein. TIG1 interaction stablilized Axl by inhibiting its proteasome-dependent degradation. TIG1-depleted IBC cells exhibited reduced Axl expression, inactivation of NF-κB and downregulation of MMP-9, indicating that TIG1 regulates invasion of IBC cells by supporting the Axl signaling pathway in IBC cells. Consistent with these results, treatment of IBC cells with the Axl inhibitor SGI-7079 decreased their malignant properties in vitro. Lastly, TIG1 expression correlated positively with Axl expression in primary human IBC specimens. Our findings establish that TIG1 positively modifies the malignant properties of IBC by supporting Axl function, advancing understanding of its development and rationalizing TIG1 and Axl as promising therapeutic targets in IBC treatment.