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Integrative Microarray Analysis of Pathways Dysregulated in Metastatic Prostate Cancer

¹ Department of Pathology, Brigham and Women's Hospital, ² Harvard Medical School, and ³ The Dana-Farber Cancer Institute, Boston, Massachusetts; ⁴ Department of Molecular Biophysics and Biochemistry, ⁵ Program in Computational Biology and Bioinformatics, and ⁶ Department of Computer Science, Yale University, New Haven, Connecticut; and ⁷ The Broad Institute of MIT and Harvard, Cambridge, Massachusetts

Requests for reprints: Mark A. Rubin, Room C 410-A, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021. Phone: 212-746-6313; E-mail: rubinma{at}med.cornell.edu.

Microarrays have been used to identify genes involved in cancer progression. We have now developed an algorithm that identifies dysregulated pathways from multiple expression array data sets without a priori definition of gene expression thresholds. Integrative microarray analysis of pathways (IMAP) was done using existing expression array data from localized and metastatic prostate cancer. Comparison of metastatic cancer and localized disease in multiple expression array profiling studies using the IMAP approach yielded a list of about 100 pathways that were significantly dysregulated (P < 0.05) in prostate cancer metastasis. The pathway that showed the most significant dysregulation, HIV-I NEF, was validated at both the transcript level and the protein level by quantitative PCR and immunohistochemical analysis, respectively. Validation by unsupervised analysis on an independent data set using the gene expression signature from the HIV-I NEF pathway verified the accuracy of our method. Our results indicate that this pathway is especially dysregulated in hormone-refractory prostate cancer. [Cancer Res 2007;67(21):10296–303]