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TGFBR1*6A enhances the migration and invasion of MCF-7 breast cancer cells through RhoA activation.

Abstract
TGFBR1*6A is a common hypomorphic variant of the type 1 transforming growth factor beta receptor (TGFBR1), which has been associated with increased cancer risk in some studies. Although TGFBR1*6A is capable of switching TGF-beta 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-beta 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-beta signaling-independent manner.
AuthorsDiana S Rosman, Sharbani Phukan, Chiang-Ching Huang, Boris Pasche
JournalCancer research (Cancer Res) Vol. 68 Issue 5 Pg. 1319-28 (Mar 01 2008) ISSN: 1538-7445 [Electronic] United States
PMID18316594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, Transforming Growth Factor beta
  • RHOA protein, human
  • Protein Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse
  • rhoA GTP-Binding Protein
Topics
  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neoplasm Invasiveness
  • Protein Serine-Threonine Kinases (genetics, physiology)
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta (genetics, physiology)
  • Signal Transduction
  • rhoA GTP-Binding Protein (genetics, metabolism, physiology)

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