Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania, USA.
Cancer Res. 2010 Dec 1;70(23):9671-81. doi: 10.1158/0008-5472.CAN-10-2177. Epub 2010 Nov 23.
Gadd45a plays a pivotal role as a stress sensor that modulates cellular responses to various stress stimuli including oncogenic stress. We reported that the stress sensor Gadd45a gene functions as a tumor suppressor in Ras-driven breast tumorigenesis via increasing JNK-mediated apoptosis and p38-mediated senescence. In contrast, here, we show that Gadd45a promotes Myc-driven breast cancer by negatively regulating MMP10 via GSK3 β/β-catenin signaling, resulting in increased tumor vascularization and growth. These novel findings indicate that Gadd45a functions as either tumor promoter or suppressor, is dependent on the oncogenic stress, and is mediated via distinct signaling pathways. Collectively, these novel findings highlight the significance of the type of oncogenic alteration on how stress response genes function during initiation and progression of tumorigenesis. Because Gadd45a is a target for BRCA1 and p53, these findings have implications regarding BRCA1/p53 tumor suppressor functions.
Gadd45a 作为一种应激传感器发挥着关键作用，调节细胞对各种应激刺激的反应，包括致癌应激。我们报道称，应激传感器 Gadd45a 基因通过增加 JNK 介导的细胞凋亡和 p38 介导的衰老，作为 Ras 驱动的乳腺癌发生中的肿瘤抑制因子发挥作用。相比之下，在这里，我们表明 Gadd45a 通过 GSK3β/β-catenin 信号通路负调控 MMP10，促进 Myc 驱动的乳腺癌，从而增加肿瘤血管生成和生长。这些新发现表明，Gadd45a 作为肿瘤促进剂或抑制剂的功能取决于致癌应激，并通过不同的信号通路介导。总之，这些新发现强调了致癌改变的类型如何影响应激反应基因在肿瘤发生的起始和进展过程中的功能。因为 Gadd45a 是 BRCA1 和 p53 的靶标，这些发现与 BRCA1/p53 肿瘤抑制因子的功能有关。
