Oncotarget

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AKT1/BRCA1 in the control of homologous recombination and genetic stability: the missing link between hereditary and sporadic breast cancers

Josée Guirouilh-Barbat _, Therese Wilhelm and Bernard S. Lopez

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Oncotarget. 2010; 1:691-699. https://doi.org/10.18632/oncotarget.203

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Abstract

Received: September 24, 2010, Accepted: December 16, 2010, Published: December 16, 2010

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.

 


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