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Identification of Genes Required for the Survival of BRCA 1-/- Cells

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Annual rept. 1 Feb 2010-31 Jan 2011

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A major obstacle for breast cancer drug discovery is target identification. Despite the wealth of information on copy number alterations and mutations recently available from sequencing efforts such as The Cancer Genome Atlas, identifying new targets for breast cancer therapeutics has proved challenging because causative perturbations cannot be determined from benign changes without functional studies. Genetic shRNA screens are powerful tools for identifying loss-of-function phenotypes in mammalian cells and can be used to complement sequencing efforts in the identification of new drug targets. To perform such screens, we have developed bar-coded shRNA libraries in retroviral and lentiviral vectors that target the entire human genome. Our proposal aims to use this novel screening technology to identify new therapeutic targets for breast cancers harboring BRCA1 mutations. Towards this end, we aim to identify and characterize genes that are selectively required for proliferation and survival of breast cancer cells with BRCA1 loss-of-function mutations but not required for viability of isogenic breast cancer cells expressing wild-type, functional BRCA1. These genes, called BSLs for BRCA1 Synthetic Lethal genes, are essential in cells lacking BRCA1, and as such are prime targets for therapeutic intervention to treat breast cancers that harbor a loss of BRCA1 function. We have accomplished the isolation of isogenic cell lines that differ only in their BRCA1 genes, one with wild-type levels of functional BRCA1 and one with a mutant BRCA1 gene. We have shown that these cells are differentially sensitive to DNA damage in the form of ionizing radiation. Cells carrying a mutant BRCA1 are more IR-sensitive than their complemented wild-type counterparts. We have begun to perform the synthetic lethal shRNA screen on these two cell liens using our barcoded shRNA library.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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