title: 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.
authors.affiliation: Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 880, Chicago, IL 60611, USA.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Rosman
authors.forename: Sharbani
authors.initials: S
authors.lastname: Phukan
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C066737:RHOA protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D020742:rhoA GTP-Binding Protein