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

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 wi...

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Bibliographic Details
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
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-13-0967