Plo Isabelle, Laulier Corentin, Gauthier Laurent, Lebrun Fabienne, Calvo Fabien, Lopez Bernard S
Unité Mixte de Recherche Commissariat à l'Energie Atomique (CEA)-Centre National de la Recherche Scientifique (CNRS) 217, Fontenay aux Roses, 92265, France.
Cancer Res. 2008 Nov 15;68(22):9404-12. doi: 10.1158/0008-5472.CAN-08-0861.
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.
AKT1在散发性乳腺癌中经常上调，而BRCA1在家族性乳腺癌中经常发生突变。由于BRCA1参与同源重组（HR），我们研究了AKT1是否也对这一过程有影响。我们发现AKT1通过将BRCA1和RAD51蛋白滞留在细胞质中来抑制HR，从而导致类似BRCA1缺陷的表型。这一过程并不需要AKT1直接对BRCA1进行磷酸化。BRCA1和RAD51的细胞质滞留与肿瘤细胞系以及散发性乳腺癌活检组织中激活的AKT1相关。在非病理条件下，激活AKT1并刺激成纤维细胞增殖的成纤维细胞生长因子会削弱过度的HR，但不会完全抑制它，从而促进基因组稳定性。我们的研究表明，在高比例的散发性乳腺癌中，BRCA1和RAD51的调控发生改变，并突出了细胞外AKT信号依赖的HR和基因组稳定性调控作用。
