Abstract
AKT1 is frequently up-regulated in sporadic breast cancer, whereas BRCA1 is frequently mutated in familial breast cancer. Because BRCA1 is involved in homologous recombination (HR), we addressed whether AKT1 also has an effect on this process. We showed that AKT1 repressed HR through cytoplasmic retention of BRCA1 and RAD51 proteins, resulting in a BRCA1-deficient-like phenotype. This process does not require direct BRCA1 phosphorylation by AKT1. The cytoplasmic retention of BRCA1 and RAD51 correlated with activated AKT1 in tumor cell lines and in biopsies from sporadic breast cancers. Under nonpathologic conditions, fibroblast growth factor, which activates AKT1 and stimulates proliferation in fibroblasts, impaired excessive HR without fully inhibiting it, promoting genome stability. Our study reveals that the regulation of BRCA1 and RAD51 is altered in a high frequency of sporadic breast cancers and highlights the role of extracellular AKT signaling-dependent regulation of HR and genome stability.
Highlights
Homologous recombination (HR), is a fundamental, evolutionarily conserved process involved in the variability/stability balance of the genome
A very precise regulation of HR is essential to maintain the equilibrium between stability and diversification of the genome
Cells expressing a dominant-negative form of RAD51, which poisons HR, produce more tumors when injected into nude mice [5]
Summary
Homologous recombination (HR), is a fundamental, evolutionarily conserved process involved in the variability/stability balance of the genome. HR is implicated in gene diversification, molecular evolution, chromosome segregation during meiosis, DNA repair, and resumption of stalled replication forks. A very precise regulation of HR is essential to maintain the equilibrium between stability and diversification of the genome. Uncontrolled excess HR can lead to genetic changes and genome rearrangements BRCA1 and BRCA2, two partners of RAD51 involved in HR [11,12,13,14,15], are frequently mutated in hereditary breast and ovarian cancers [16, 17]. HR is part of the DNA damage response and most germ line mutations responsible for familial breast cancer involve genes implicated in the DNA damage
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