title: TIG1 promotes the development and progression of inflammatory breast cancer through activation of Axl kinase.
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.
authors.affiliation: 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.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Hitomi
authors.initials: H
authors.lastname: Saso
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Yun
authors.initials: Y
authors.lastname: Gong
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
authors.forename: Steven L
authors.initials: SL
authors.lastname: Warner
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D058922:Inflammatory Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D056892:Mediator Complex / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C416944:MED15 protein, human; D056892:Mediator Complex; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase