PDF(Pubmed)
Abstract：
The association of BRCA1 and BRCA2 mutations with increased risk for developing epithelial ovarian cancer is well established. However, the observed clinical differences, particularly the improved therapy response and patient survival in BRCA2-mutant patients, are unexplained. Our objective is to identify molecular pathways that are differentially regulated upon the loss of BRCA1 and BRCA2 functions in ovarian cancer. Transcriptomic and pathway analyses comparing BRCA1-mutant, BRCA2-mutant, and homologous recombination wild-type ovarian tumors showed differential regulation of the Wnt/β-catenin pathway. Using Wnt3A-treated BRCA1/2 wild-type, BRCA1-null, and BRCA2-null mouse ovarian cancer cells, we observed preferential activation of canonical Wnt/β-catenin signaling in BRCA1/2 wild-type ovarian cancer cells, whereas noncanonical Wnt/β-catenin signaling was preferentially activated in the BRCA1-null ovarian cancer cells. Interestingly, BRCA2-null mouse ovarian cancer cells demonstrated a unique response to Wnt3A with the preferential upregulation of the Wnt signaling inhibitor Axin2. In addition, decreased phosphorylation and enhanced stability of β-catenin were observed in BRCA2-null mouse ovarian cancer cells, which correlated with increased inhibitory phosphorylation on GSK3β. These findings open venues for the translation of these molecular observations into modalities that can impact patient survival.
UNASSIGNED: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/β-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.
UNASSIGNED: We show that BRCA1 and BRCA2 mutation statuses differentially impact the regulation of the Wnt/β-catenin signaling pathway, a major effector of cancer initiation and progression. Our findings provide a better understanding of molecular mechanisms that promote the known differential clinical profile in these patient populations.
摘要：
BRCA1和BRCA2突变与发生上皮性卵巢癌的风险增加的相关性已得到证实。然而,观察到的临床差异，特别是BRCA2突变(BRCA2mt)患者的治疗反应和患者生存期的改善是无法解释的.我们的目标是确定在卵巢癌中BRCA1和BRCA2功能丧失时差异调节的分子途径。转录组学和通路分析比较BRCA1突变体（BRCA1mt），BRCA2mt和同源重组野生型（HRwt）卵巢肿瘤显示出Wnt/β-catenin途径的差异调节。使用Wnt3A处理的BRCA1/2野生型（BRCAwt），BRCA1null和BRCA2null小鼠卵巢癌细胞，我们观察到BRCAwt卵巢癌细胞中经典Wnt/β-catenin信号优先激活，而BRCA1null细胞中的非经典Wnt/β-catenin信号优先激活。有趣的是,BRCA2null小鼠卵巢癌细胞，显示了对Wnt3A的独特反应，Wnt信号传导抑制剂优先上调，Axin2.此外,在BRCA2null小鼠卵巢癌细胞中观察到β-catenin的磷酸化降低和稳定性增强，这与GSK3β的抑制磷酸化增加有关。这些发现为将这些分子观察转化为可能影响患者生存的模式开辟了场所。
