Abstract
BackgroundDevelopment 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.MethodsSpecimens 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.ResultsTumour 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.ConclusionHigh 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.
Highlights
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
High expression levels of Trio, Vav1 and TIAM-1 were seen in breast tumours, especially in those with poor prognosis
The Rho GTPases, which function as guanine nucleotide regulated binary switches, control the regulation of the actin cytoskeleton, and as such, have been implicated in promoting a variety of cellular processes including cell motility and migration, changes in cell adhesion as well as actin cytoskeletal reorganisation [1,2,3] and gene expression/transcription [4]
Summary
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. During the development of metastasis in breast cancer, tumour cells undergo numerous changes in their cytoskeletal structure and gene expression promoting changes in cell adhesion, motility and morphology leading to metastasis and tissue invasion. The Rho GTPases, which function as guanine nucleotide regulated binary switches, control the regulation of the actin cytoskeleton, and as such, have been implicated in promoting a variety of cellular processes including cell motility and migration, changes in cell adhesion as well as actin cytoskeletal reorganisation [1,2,3] and gene expression/transcription [4]. The GTPases bind free cytoplasmic GTP to become reactivated
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