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.