TGFBR1*6A Enhances the Migration and Invasion of MCF-7 Breast Cancer Cells through RhoA Activation
| Autor: | Diana S. Rosman, Sharbani Phukan, Chiang Ching Huang, Boris Pasche |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Cancer Research RHOA Receptor Transforming Growth Factor-beta Type I Protein Serine-Threonine Kinases Article Mice Cell Movement Cell Line Tumor Animals Humans Neoplasm Invasiveness Extracellular Signal-Regulated MAP Kinases Cell Proliferation Oncogene biology Cell growth Gene Expression Profiling Cell migration Transfection Transforming growth factor beta Enzyme Activation Gene Expression Regulation Neoplastic Oncology Cancer research biology.protein NIH 3T3 Cells Signal transduction rhoA GTP-Binding Protein Receptors Transforming Growth Factor beta Signal Transduction |
| Popis: | TGFBR1*6A is a common hypomorphic variant of the type 1 transforming growth factor β receptor (TGFBR1), which has been associated with increased cancer risk in some studies. Although TGFBR1*6A is capable of switching TGF-β growth-inhibitory signals into growth-stimulatory signals when stably transfected into MCF-7 breast cancer cells, the biological effects of TGFBR1*6A are largely unknown. To broadly explore the potential oncogenic properties of TGFBR1*6A, we assessed its effects on NIH-3T3 cells as well as its effect on the migration and invasion of MCF-7 cells. We found that TGFBR1*6A has decreased oncogenic properties compared with TGFBR1. However, TGFBR1*6A significantly enhances MCF-7 cell migration and invasion in a TGF-β signaling–independent manner. Gene expression profiling studies identified two down-regulated genes involved in cell migration and invasion: ARHGAP5, encoding ARHGAP5, and FN1, encoding fibronectin-1 (FN1). ARHGAP5 and FN1 expression was similarly down-regulated in MCF-7 cells stably transfected with a kinase-inactivated TGFBR1*6A construct. Functional assays show that TGFBR1*6A-mediated decreased ARHGAP5 expression is associated with higher RhoA activation, a crucial mediator of cell migration. Extracellular signal-regulated kinase (ERK) activation is also higher in cells that harbor the TGFBR1*6A allele. We conclude that TGFBR1*6A is not an oncogene but enhances MCF-7 cell migration and invasion through RhoA and ERK pathway activation and down-regulates two crucial mediators of this phenotype. These results provide the first evidence that TGFBR1*6A may contribute to cancer progression in a TGF-β signaling–independent manner. [Cancer Res 2008;68(5):1319–28] |
| Databáze: | OpenAIRE |
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