The expression and prognostic value of the guanine nucleotide exchange factors (GEFs) Trio, Vav1 and TIAM-1 in human breast cancer

BACKGROUND Development of metastasis in breast cancer is a multi-step process comprising changes in cytoskeletal structure and gene expression of tumour cells leading to changes in cell adhesion and motility. The Rho GTPase proteins, which function as guanine nucleotide regulated binary switches, govern a variety of cellular processes including cell motility and migration, changes in cell adhesion as well as actin cytoskeletal reorganisation and gene expression/transcription. One group of activators which regulate the Rho-GTPases is the guanine nucleotide exchange factors (GEFs), and this study looked at three such GEFs, Trio, Vav1 and TIAM-1. The purpose of this study was to investigate the expression of these GEFs, in human breast cancer and assess the affect on clinical outcome. METHODS Specimens of fresh, frozen breast tumour tissue (n = 113) and normal background tissue (n = 30) were processed for quantitative PCR analysis. The expression and levels of expression of Trio, Vav1 and TIAM-1 were analysed using RT-PCR and real-time Q-PCR respectively. Sections were also immunostained with Trio and Tiam-1 antibodies. RESULTS Tumour tissue exhibited high levels of all three Rho activators Trio, Vav1 and TIAM-1 compared with normal background breast tissue, reaching a level of significance for the GEF Trio (p = 0.013). Trio levels also increased significantly in patients with a poor prognostic index (p = 0.04).Levels of TIAM-1 were significantly higher in tumour tissue from patients who died from breast cancer compared with those who survived (p = 0.04). No significant correlation was found between tumour grade and histology types. CONCLUSION High expression levels of Trio, Vav1 and TIAM-1 were seen in breast tumours, especially in those with poor prognosis. This suggests that aberrant regulation of Rho family activities by GEFs may have an important prognostic value in breast cancer.