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Cancer Res. 2008 Mar 1;68(5):1319-28. doi: 10.1158/0008-5472.CAN-07-5424.

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

Author information

1
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.

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.

PMID:
18316594
PMCID:
PMC2673101
DOI:
10.1158/0008-5472.CAN-07-5424
[Indexed for MEDLINE]
Free PMC Article

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