Pickard, MR and Green, AR and Ellis, IO and Caldas, C and Hedge, VL and Mourtada-Maarabouni, M and Williams, GT (2009) Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Research, 11 (4). R60 -?. ISSN 1465-542X

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Abstract

INTRODUCTION: Programmed cell death through apoptosis plays an essential role in the hormone-regulated physiological turnover of mammary tissue. Failure of this active gene-dependent process is central both to the development of breast cancer and to the appearance of the therapy-resistant cancer cells that produce clinical relapse. Functional expression cloning in two independent laboratories has identified Finkel-Biskis-Reilly murine sarcoma virus-associated ubiquitously expressed gene (Fau) as a novel apoptosis regulator and candidate tumour suppressor. Fau modifies apoptosis-controller Bcl-G, which is also a key target for candidate oncoprotein maternal embryonic leucine zipper kinase (MELK). METHODS: We have used RNA interference to downregulate Fau and Bcl-G expression, both simultaneously and independently, in breast cancer cells in vitro to determine the importance of their roles in apoptosis. Expression of Fau, Bcl-G and MELK was measured by quantitative RT-PCR in breast cancer tissue and in matched breast epithelial tissue from the same patients. Expression data of these genes obtained using microarrays from a separate group of patients were related to patient survival in Kaplan-Meier analyses. RESULTS: siRNA-mediated downregulation of either Fau or Bcl-G expression inhibited apoptosis, and the inhibition produced by combining the two siRNAs was consistent with control of Bcl-G by Fau. Fau expression is significantly reduced in breast cancer tissue and this reduction is associated with poor patient survival, as predicted for a candidate breast cancer tumour suppressor. In addition, MELK expression is increased in breast cancer tissue and this increase is also associated with poor patient survival, as predicted for a candidate oncogene. Bcl-G expression is reduced in breast cancer tissue but decreased Bcl-G expression showed no correlation with survival, indicating that the most important factors controlling Bcl-G activity are post-translational modification (by Fau and MELK) rather than the rate of transcription of Bcl-G itself. CONCLUSIONS: The combination of in vitro functional studies with the analysis of gene expression in clinical breast cancer samples indicates that three functionally interconnected genes, Fau, Bcl-G and MELK, are crucially important in breast cancer and identifies them as attractive targets for improvements in breast cancer risk prediction, prognosis and therapy.

Item Type: Article
Uncontrolled Keywords: Adenocarcinoma, Apoptosis, Breast Neoplasms, Cell Line, Tumor, Epithelial Cells, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Neoplasm Proteins, Prognosis, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, RNA Interference, RNA, Small Interfering, Ribosomal Proteins, Tumor Stem Cell Assay, Ultraviolet Rays
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
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Depositing User: Symplectic
Date Deposited: 11 Jan 2017 11:46
Last Modified: 11 Jan 2017 11:46
URI: http://eprints.keele.ac.uk/id/eprint/2749

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