In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene
In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene
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DOI：
10.1073/pnas.1311909111
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发表时间：
2014-01-21
影响因子：
11.1
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
--
作者：
Dunn, Gavin P.;Cheung, Hiu Wing;Hahn, William C.
高级别浆液性卵巢癌的特征是广泛复发的拷贝数改变。尽管一些拷贝数改变的区域含有已知的癌基因和肿瘤抑制基因，但卵巢癌中大多数扩增或缺失区域所靶向的基因仍不明确。在这里，我们系统地测试了扩增的基因的能力，以促进肿瘤形成的体内多重转化测定。我们确定GRB 2相关结合蛋白2（GAB 2）作为一个反复扩增的基因，有效地转化永生化的卵巢和输卵管分泌上皮细胞。过表达GAB 2的癌细胞系需要GAB 2才能存活，并显示出磷脂酰肌醇3-激酶（PI 3 K）途径活化的证据，这是GAB 2诱导转化所需的。过表达GAB 2的细胞系与携带突变型PIK 3CA的细胞系一样对PI 3 K抑制敏感。总之，这些观察结果将GAB 2命名为卵巢癌癌基因，确定了激活PI 3 K信号传导的替代机制，并强调了PI 3 K信号传导在这种癌症中的重要性
High-grade serous ovarian cancers are characterized by widespread recurrent copy number alterations. Although some regions of copy number change harbor known oncogenes and tumor suppressor genes, the genes targeted by the majority of amplified or deleted regions in ovarian cancer remain undefined. Here we systematically tested amplified genes for their ability to promote tumor formation using an in vivo multiplexed transformation assay. We identified the GRB2-associated binding protein 2 (GAB2) as a recurrently amplified gene that potently transforms immortalized ovarian and fallopian tube secretory epithelial cells. Cancer cell lines overexpressing GAB2 require GAB2 for survival and show evidence of phosphatidylinositol 3-kinase (PI3K) pathway activation, which was required for GAB2-induced transformation. Cell lines overexpressing GAB2 were as sensitive to PI3K inhibition as cell lines harboring mutant PIK3CA. Together, these observations nominate GAB2 as an ovarian cancer oncogene, identify an alternative mechanism to activate PI3K signaling, and underscore the importance of PI3K signaling in this cancer