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

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.

Citation

Pickard, M. R., Green, A. R., Ellis, I. O., Caldas, C., Hedge, V. L., Mourtada-Maarabouni, M., & Williams, G. T. (2009). Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Research, Article R60. https://doi.org/10.1186/bcr2350

• Journal Article Type: Article
• Acceptance Date: Aug 11, 2009
• Publication Date: Aug 11, 2009
• 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