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Uncovering Functionally Relevant Signaling Pathways Using Microarray-Based Expression Profiling

The Queen's University of Belfast Cancer Research Centre and Belfast City Hospital Trust, Belfast, Ireland

Correspondence: D. Paul Harkin, M.D., The Queen's University of Belfast Cancer Research Centre, Belfast City Hospital, Lisburn Road, Belfast 9, Ireland. Telephone 44-1232-263911; Fax: 44-28-90-263744.

The introduction of microarray technology to the scientific and medical communities has fundamentally altered the way in which we now address basic biomedical questions. Microarrays technology facilitates a more complete and inclusive experimental approach where alterations in the transcript level of entire genomes can be simultaneously assayed in response to a variety of stimuli. Conceptually different approaches to the development of microarray technology have resulted in the generation of two different array formats: oligonucleotide arrays and cDNA arrays.

The application of microarray and related technologies to identify specific targets of defined genes that have clearly been implicated in cancer progression requires a specific experimental approach. The objective of this approach is to define changes in transcriptional profile that occur in response to modulating the expression level of the gene to be studied. The resulting altered expression profile can then be viewed as a blueprint by which that gene effects its cellular function.

We have used oligonucleotide array-based expression profiling in collaboration with Affymetrix to identify downstream transcriptional targets of the BRCA1 tumor-suppressor gene as a means of defining its function. BRCA1 has been implicated in at least three functional pathways, namely, mediating the cellular response to DNA damage, as a cell cycle checkpoint protein and in the regulation of transcription. The physiological significance of these properties and their implications for the function of BRCA1 as a tumor-suppressor gene remain to be defined.

Key Words. Oligonucleotide arrays • Expression profiling • BRCA1 • Target genes • GADD45

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