TIG1 Promotes the Development and Progression of Inflammatory Breast Cancer through Activation of Axl Kinase

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-11, Vol.73 (21), p.6516-6525
• Main Authors: XIAOPING WANG, SASO, Hitomi, HORTOBAGYI, Gabriel N, HUNG, Mien-Chie, UENO, Naoto T, IWAMOTO, Takayuki, WEIYA XIA, YUN GONG, PUSZTAI, Lajos, WOODWARD, Wendy A, REUBEN, James M, WARNER, Steven L, BEARSS, David J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Blotting, Western; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Disease Progression; Female; Fluorescent Antibody Technique; Gynecology. Andrology. Obstetrics; Humans; Immunoprecipitation; Inflammatory Breast Neoplasms - metabolism; Inflammatory Breast Neoplasms - pathology; Inflammatory Breast Neoplasms - prevention & control; Mammary gland diseases; Mediator Complex - antagonists & inhibitors; Mediator Complex - genetics; Mediator Complex - metabolism; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Pharmacology. Drug treatments; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Real-Time Polymerase Chain Reaction; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction; Tumor Cells, Cultured; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-0967

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.