Abstract
Endogenous replicative stress could be one trigger leading to tumor initiation: indeed, activation of the DNA damage response (DDR), considered the result of replicative stress, is observed in pre-cancerous cells; moreover, in hereditary breast cancers, almost all of the genes affected relate to the DDR. The most frequently mutated gene in hereditary breast cancers, BRCA1, is essential for homologous recombination (HR), a fundamental process for maintaining genome stability that permits the reactivation of blocked replication forks . Recent studies have established links between DDR and the oncogenic kinase AKT1, which is upregulated in about 50% of sporadic breast cancers. More specifically, the activation of AKT1 shows a deficient phenotype in BRCA1 and HR, revealing molecular similarities between hereditary and sporadic breast cancers. However, these results reveal a paradox regarding the physiological role of AKT1: in non-tumor cells, AKT1 promotes cellular proliferation, but consequently endangers genome integrity during replication if HR is inhibited. Since HR could itself lead to genetic instability, we propose that, under physiological conditions, moderate activation of AKT1 does not inhibit but prevents an excess of HR. The regulation of AKT1 would represent a fine transitory system for controlling HR and maintaining genomic integrity.
Highlights
The coordination of a complex network of metabolic pathways ensures continued maintenance, duplication, and transmission of the genome
DNA replication forks are regularly blocked by a variety of endogenous stresses that can result from bulging regions in the DNA, regions of hybrid DNA/RNA, and from endogenous metabolism of the cell [1]
The prolonged arrest of these replication forks leads to the formation of double-strand breaks (DSBs) in the DNA, which can be taken care of by homologous recombination (HR) and non-homologous end-joining (NHEJ) [2,3,4]
Summary
The coordination of a complex network of metabolic pathways ensures continued maintenance, duplication, and transmission of the genome. Among the 11 genes whose germline mutations are responsible for predispose to familial breast cancer, 10 are implicated in the DDR pathway [10,11].
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