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Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer

Pickard, Mark R; Green, Andrew R; Ellis, Ian O; Caldas, Carlos; Hedge, Vanessa L; Mourtada-Maarabouni, Mirna; Williams, Gwyn T

Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer Thumbnail


Authors

Mark R Pickard

Andrew R Green

Ian O Ellis

Carlos Caldas

Vanessa L Hedge

Gwyn T Williams



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.

Journal Article Type Article
Acceptance Date Aug 11, 2009
Publication Date Aug 11, 2009
Publicly Available Date Mar 29, 2024
Journal Breast Cancer Research
Print ISSN 1465-5411
Publisher Springer Verlag
Article Number R60
ISBN 14655411 1465542X
DOI https://doi.org/10.1186/bcr2350
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-S
Publisher URL http://dx.doi.org/10.1186/bcr2350

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