TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase

Xiaoping Wang, Hitomi Saso, Takayuki Iwamoto, Weiya Xia, Yun Gong, Lajos Pusztai, Wendy A. Woodward, James M. Reuben, Steven L. Warner, David J. Bearss, Gabriel N. Hortobagyi, Mien Chie Hung, Naoto T. Ueno

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6516-6525
Number of pages10
JournalCancer Research
Volume73
Issue number21
DOIs
Publication statusPublished - Nov 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wang, X., Saso, H., Iwamoto, T., Xia, W., Gong, Y., Pusztai, L., Woodward, W. A., Reuben, J. M., Warner, S. L., Bearss, D. J., Hortobagyi, G. N., Hung, M. C., & Ueno, N. T. (2013). TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase. Cancer Research, 73(21), 6516-6525. https://doi.org/10.1158/0008-5472.CAN-13-0967