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 Identification of a breast cancer associated regulatory network

Jeffrey D. Parvin, Zeina Kais, Mansi Arora, Shweta Kotian, Alicia Zha, Derek Ransburgh, Doruk Bozdag, Umit Catalyurek, and Kun Huang

Department of Biomedical Informatics and the Comprehensive Cancer Center,
Ohio State University, Columbus, OH


Abstract:
This project tests a new framework for discovery of genes involved in the breast carcinogenesis process. Among families that have a predisposition to breast cancer, approximately 25% have inherited mutations in either breast cancer associated ("BRCA") genes BRCA1 or BRCA2, but the predisposing mutated genes in the majority of the families are unknown.  BRCA1 and BRCA2 gene products both regulate cellular pathways that involve DNA repair and centrosome duplication, and their expression is correlated in microarray analyses in many cell types.  We hypothesize that other unidentified BRCA genes may be involved in the same pathways that BRCA1 and BRCA2 regulate, and thus may be discovered by identifying genes whose expression also is correlated with that of BRCA1 and BRCA2.  We interrogate public-domain gene expression databases using newly developed computational tools that include combinatorial and algebraic clustering methods to identify genes whose expression correlates with these tumor suppressors.  Identified genes are then tested in the laboratory.  RNA interference is used to disrupt the expression of the candidate BRCA gene products in two cell-based assays that are dependent on BRCA1 and BRCA2 expression.  The first assay models the regulation of homology-directed recombination repair of double-strand DNA breaks, and the second assay tests the control of duplication of the centrosome. We have selected nine genes that tightly cluster with BRCA1 and BRCA2 expression in multiple datasets, and these nine genes have never before been linked with the two reference genes.   In summary, we employ a novel experimental framework that develops new bioinformatic tools for identifying candidate genes whose regulation suggests the potential for involvement in breast carcinogenesis, and we validate the gene in the lab.  When tested in the lab using RNA interference to deplete the specific protein, six of these genes were found to affect homologous recombination and four affected the regulation of centrosome number. If the informatics analysis is considered a screening tool to find genes/proteins involved in breast carcinogenesis, then this approach has an extremely high success rate in finding proteins that impact phenotypes regulated by BRCA1 and BRCA2. This experimental framework may also be applicable to the identification of networks of genes involved in common pathways in other disease processes.

Sponsored by the Russ College of Engineering and Technology’s School of Electrical Engineering and Computer Science;
Biomedical Engineering program; Center for Intelligent, Distributed and Dependable Systems; and Bioinformatics Laboratory;
the College of Arts and Sciences’ Molecular and Cellular Biology program;
the Ohio University Genomics Facility; The Edison Biotechnical Institute; and Diagnostic Hybrids, Inc.

Jeffrey D. Parvin, M.D., Ph.D.

Jeff Parvin received a Ph.D. in microbiology and an M.D. from Mt. Sinai School of Medicine in 1989. For his Ph.D., Dr. Parvin studied the evolution of influenza viruses, and he developed methods for modifying the genome of the virus.  From 1989-94, Dr. Parvin was a postdoctoral fellow in the laboratory of Phillip A. Sharp at MIT where he focused on the biochemistry of gene expression.  From 1995 to 2007, Dr. Parvin was an Assistant Professor and then an Associate Professor at Harvard Medical School and based in the Brigham and Women’s Hospital.  While at Harvard Medical School, Dr. Parvin continued the study of the biochemistry of gene expression and developed an interest in the breast cancer associated tumor suppressor, BRCA1.  Analysis of BRCA1 function in normal breast cells took the Parvin lab in new directions, including continuing studies on RNA transcription, but also DNA damage repair, function of ubiquitin ligases, and the regulation of centrosomes.  Fellows in the Parvin lab developed the only known cell-free biochemical assays regulated by the BRCA1 enzymatic activity.  Informatics methods of studying BRCA1 were begun in collaboration with the laboratory of Marc Vidal, and BRCA1 interacting proteins were inferred from gene expression data, and subsequently biologically confirmed.  In 2007, Dr. Parvin joined the department of Biomedical Informatics and the cancer center at Ohio State University where he is starting the Systems Biology division.  Continuing efforts in the Parvin lab are focused on using informatics methods to find proteins that participate in the same pathways as does BRCA1. In addition, the Parvin lab is developing proteomic methods for analyzing BRCA1 function. In 2008, Dr. Parvin became the director of the biomedical informatics shared resource at the OSU cancer center, and he is the interim-chair of the Biomedical Informatics Department.

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