Journal Article

Synthetic lethality between CCNE1 amplification and loss of BRCA1

Hahn, William C., Mitchell, Gillian, D'Andrea, Alan D., George, Joshy, Davis, Sally, Alsop, Kathryn, Weir, Barbara A., Au-Yeung, George, Simpson, Kaylene, Etemadmoghadam, Dariush, Bowtell, David D. L.

2013

Overview

High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1 -amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1 -amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1 -amplified tumors.

• Publisher: National Academy of Sciences,NATIONAL ACADEMY OF SCIENCES,National Acad Sciences
• Subject: animal ovaries / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biological Sciences / Boronic Acids - pharmacology / Boronic Acids - therapeutic use / Bortezomib / BRCA1 Protein - genetics / Breast cancer / Cancer / Cell lines / cross-linking reagents / Cyclin E - genetics / Cyclin E - metabolism / cyclins / Female / gene amplification / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / Genetic mutation / Genetic screening / Genomics / homologous recombination / Homologous Recombination - drug effects / Humans / Inactivation / Inhibitor drugs / Microarray Analysis / Mutation / neoplasm cells / Oncogene Proteins - genetics / Oncogene Proteins - metabolism / Ovarian cancer / ovarian neoplasms / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - genetics / patients / platinum / proteasome endopeptidase complex / Proteasome Endopeptidase Complex - drug effects / Pyrazines - pharmacology / Pyrazines - therapeutic use / Ribonucleic acid / RNA / RNA, Small Interfering - genetics / Small interfering RNA / Transfection / Tumor cell line / tumor suppressor proteins / Tumors / ubiquitin / Viability