Breast cancer is a biologically and clinically heterogeneous disease that makes clinical management challenging. Cancer genomics can identify candidate genetic lesions, but functional studies are required to dissect which changes impact disease progression, treatment efficacy, and development of resistance. Core B was conceived to facilitate functional studies in breast cancer by introducing state-of-the-art RNA interference technology to the Program Project. It will incorporate and implement new technology developed by Dr. Scott Lowe (the core leader) and Dr. Gregory Hannon (CSHL) based on RNA interference mediated by short hairpin RNAs (shRNAs). The core concentrates its efforts on providing shRNAs expressed from the miR-30 scaffold which Drs. Lowe and Hannon have optimized over the last 7 years as a tool to potently and reversibly repress gene expression in cultured cells and in animals. This team has also developed powerful strategies for regulated RNAi to inducibly suppress gene expression, as well as phenotype-based screens using multiplexed RNAi formats;they also have developed rapid methods for producing inducible shRNA transgenic mice for spatial, temporal, and reversible control of the expression of any gene, in vivo. Core B will provide such advanced RNAi tools to program investigators, and continue to develop and optimize RNAi methodology for controlling gene function in breast cancer models. These services will be broadly divided into two components, the first, involving vector production and screening services and, the second, support for production of inducible shRNA transgenic mice. Among these services include the implementation of an RNAi sensor assay that enables the identification of highly potent shRNAs against genes of interest. The Core will benefit from existing infrastructure at MSKCC and interact with each of the proposed Projects, thus providing cost effective services and a source of interaction for the Program. Implementation of the RNAi tools provided by this core is expected to advance the ability to functional studies throughout the Program, and will stimulate the development of new technologies (shRNA libraries, and mouse models) that will be useful for the breast cancer research community
Core B will provide innovative RNAi tools to Project members for performing function studies in cultured cells and in mice, thereby adding new technology to facilitate both the discovery and mechanistic efforts of in the Program. Studies using shRNA transgenic mice have the ability to revolutionize breast cancer animal modeling by enabling the spatial, temporal, and reversible control of endogenous gene expression to study breast cancer initiation and maintenance
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