TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties
| Autor: | Swathi Karthikeyan, Josh Donaldson, David Marc Rosen, Kelly Kyker-Snowman, Konstantinos Konstantopoulos, Sarah Croessmann, Karen Cravero, Robert M. Hughes, Paula J. Hurley, Berry Button, Eric S. Christenson, Natasha Hunter, Christopher L. Yankaskas, Lauren Dennison, Ian Waters, Ben Ho Park |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research animal structures medicine.medical_treatment Gene Expression Breast Neoplasms Biology medicine.disease_cause Article Metastasis Targeted therapy Cell Line 03 medical and health sciences Phosphatidylinositol 3-Kinases 0302 clinical medicine Breast cancer In vivo Cell Line Tumor medicine Biomarkers Tumor Humans Receptor trkA Oncogenes medicine.disease Phenotype Immunohistochemistry 030104 developmental biology Cell Transformation Neoplastic Oncology nervous system Cell culture 030220 oncology & carcinogenesis Trk receptor Cancer research Female Mitogen-Activated Protein Kinases Carcinogenesis Signal Transduction |
| Zdroj: | Breast Cancer Res Treat |
| Popis: | BACKGROUND/PURPOSE: TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. EXPERIMENTAL DESIGN/METHODS: To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. RESULTS: TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. CONCLUSIONS: Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients. |
| Databáze: | OpenAIRE |
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