title: TrkB Promotes Breast Cancer Metastasis via Suppression of Runx3 and Keap1 Expression.
abstract: In metastatic breast cancer, the acquisition of malignant traits has been associated with the increased rate of cell growth and division, mobility, resistance to chemotherapy, and invasiveness. While screening for the key regulators of cancer metastasis, we observed that neurotrophin receptor TrkB is frequently overexpressed in breast cancer patients and breast cancer cell lines. Additionally, we demonstrate that TrkB expression and clinical breast tumor pathological phenotypes show significant correlation. Moreover, TrkB expression was significantly upregulated in basal-like, claudin-low, and metaplastic breast cancers from a published microarray database and in patients with triple-negative breast cancer, which is associated with a higher risk of invasive recurrence. Interestingly, we identified a new TrkB-regulated functional network that is important for the tumorigenicity and metastasis of breast cancer. We demonstrated that TrkB plays a key role in regulation of the tumor suppressors Runx3 and Keap1. A markedly increased expression of Runx3 and Keap1 was observed upon knockdown of TrkB, treatment with a TrkB inhibitor, and in TrkB kinase dead mutants. Additionally, the inhibition of PI3K/AKT activation significantly induced Runx3 and Keap1 expression. Furthermore, we showed that TrkB enhances metastatic potential and induces proliferation. These observations suggest that TrkB plays a key role in tumorigenicity and metastasis of breast cancer cells through suppression of Runx3 or Keap1 and that it is a promising target for future intervention strategies for preventing tumor metastasis and cancer chemoprevention.
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.
authors.forename: Won Sung
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Disease and Cell Regulation, Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406-840, Korea.|Gachon Medical Research Institute, Gil Medical Center, Incheon, 405-760, Korea.
authors.forename: Wook
authors.initials: W
authors.lastname: Jin
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB; D015398:Signal Transduction
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D008562:Membrane Glycoproteins; C493728:RUNX1 protein, human; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human
keywords: TrkB; breast cancer; keap1; metastasis; runx3