Authors' Affiliations: Department of Breast Medical Oncology, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Departments of Molecular and Cellular Oncology, Pathology, Radiation Oncology, and Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Tolero Pharmaceuticals, Inc., Salt Lake City, Utah; and Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.
Cancer Res. 2013 Nov 1;73(21):6516-25. doi: 10.1158/0008-5472.CAN-13-0967. Epub 2013 Sep 6.
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 patients with IBC. 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 matrix metalloproteinase-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. Finally, 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.
炎性乳腺癌（IBC）是最致命的乳腺癌形式，但它具有侵袭性的基础尚未完全阐明。在这项研究中，我们报告称，高肿瘤表达 TIG1（RARRES1），一种功能未知的膜蛋白，与 IBC 患者的生存率降低有关。TIG1 耗竭降低了 IBC 细胞的体外增殖、迁移和侵袭能力，并抑制了 IBC 细胞的体内肿瘤生长。我们鉴定出受体酪氨酸激酶 Axl 是 TIG1 的结合蛋白。TIG1 相互作用通过抑制其蛋白酶体依赖性降解来稳定 Axl。TIG1 耗竭的 IBC 细胞表现出 Axl 表达减少、NF-κB 失活和基质金属蛋白酶-9 的下调，表明 TIG1 通过在 IBC 细胞中支持 Axl 信号通路来调节 IBC 细胞的侵袭。与这些结果一致，用 Axl 抑制剂 SGI-7079 处理 IBC 细胞可降低其体外恶性特性。最后，TIG1 表达与原发性人 IBC 标本中的 Axl 表达呈正相关。我们的发现表明，TIG1 通过支持 Axl 功能来正向修饰 IBC 的恶性特性，从而加深了对其发展的理解，并使 TIG1 和 Axl 成为 IBC 治疗中有前途的治疗靶点。
