TGFBR1*6A Enhances the Migration and Invasion of MCF-7 Breast Cancer Cells through RhoA Activation

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]