Role of Gab2 in mammary tumorigenesis and metastasis

Yang, Ke; Wu, Di; Princen, Frédéric; Nguyên, Thành Vinh; Pang, Yuhong; Lesperance, Jacqueline; Wj, Muller; Rg, Oshima; Feng, Gong Kan

doi:10.1038/sj.onc.1210315

Cited by 80 publications

(76 citation statements)

References 24 publications

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“…Interestingly, GAB2 maps to a chromosomal region (11q13) amplified in 10-15% of breast cancers, and its Gab2 promotes anchorage-independent growth A Mira et al overexpression was confirmed in several breast cancer cell lines (Daly et al, 2002). The role of Gab2 in mammary tumor metastasis was also explored and confirmed in mouse models (Ke et al, 2007). More recently, a key role for this gene in the motility/invasion of melanoma cells and metastatic progression of melanoma was also highlighted (Horst et al, 2009).…”

Section: Discussionmentioning

confidence: 86%

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

et al. 2009

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Acquisition of independence from anchorage to the extracellular matrix is a critical event for onset and progression of solid cancers. To identify and characterize new genes conferring anchorage independence, we transduced MCF10A human normal breast cells with a retroviral cDNA expression library and selected them by growth in suspension. Microarray analysis targeted on library-derived transcripts revealed robust and reproducible enrichment, after selection, of cDNAs encoding the scaffolding adaptor Gab2. Gab2 was confirmed to strongly promote anchorageindependent growth when overexpressed. Interestingly, downregulation by RNA interference of endogenous Gab2 in neoplastic cells did not affect their adherent growth, but abrogated their growth in soft agar. Gab2-driven anchorage independence was found to specifically involve activation of the Src-Stat3 signaling axis. A transcriptional 'signature' of 205 genes was obtained from GAB2-transduced, anchorageindependent MCF10A cells, and found to contain two main functional modules, controlling proliferation and cell adhesion/migration/invasion, respectively. Extensive validation on breast cancer data sets showed that the GAB2 signature provides a robust prognostic classifier for breast cancer metastatic relapse, largely independent from existing clinical and genomic indicators and from estrogen receptor status. This work highlights a pivotal role for GAB2 and its transcriptional targets in anchorage-independent growth and breast cancer metastatic progression.

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Section: Discussionmentioning

confidence: 86%

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

et al. 2009

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“…Prior work has implicated GAB2 in NeuNT-driven murine mammary tumorigenesis and migration (16,17). However, GAB2 overexpression failed to induce the transformation of immortalized MCF10A cells (16,17). To validate our screening results, we reintroduced GAB2 into HA1E-M cells and found that tumors formed in mice at the same rate (7 of 12, 58%) as that induced by the ovarian cancer oncogene, ID4 (5) (8 of 14, 57%).…”

Section: Gab2 Transforms Immortalized Ovarian and Fallopian Tube-derivedmentioning

confidence: 96%

“…GAB2 is required for BCR/ABL-mediated transformation in chronic myeloid leukemia (CML) (31) and also HER2-mediated mammary carcinogenesis through ERK activation (16). Moreover, GAB2 is overexpressed in breast cancer (9,22) and some metastatic melanomas (24) and promotes survival in breast cancer (22) and migration in both malignancies (17,24). Several ovarian cancer cell lines also overexpress GAB2, which was linked to increased migration and the epithelial-mesenchymal transition (26).…”

Section: Discussionmentioning

confidence: 99%

Section: Gab2 Transforms Immortalized Ovarian and Fallopian Tube-derivedmentioning

confidence: 99%

“…Prior work has implicated GAB2 as a signaling intermediate in both SHP2-dependent activation of MAPK signaling (16,17) and activation of phosphatidylinositol 3-kinase (PI3K) (24). To assess the effects of suppressing GAB2 on these signaling pathways in cell lines expressing elevated or normal levels of GAB2, we interrogated the phosphorylation levels of PI3K/AKT/mTOR pathway components AKT1 and S6 as well as the MAPK pathway component ERK.…”

Section: Gab2 Transforms Immortalized Ovarian and Fallopian Tube-derivedmentioning

confidence: 99%

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In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

Dunn

Cheung

Agarwalla

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance High-grade serous ovarian cancers are characterized by widespread gain and loss of copy number involving large numbers of genes; however, the functional consequences of many of these changes remain unclear. To determine which of the many amplified genes exhibited tumor-promoting behavior, we developed a novel in vivo method to systematically screen potential oncogenes for tumor formation. We identified GAB2, a signaling adaptor protein, as a potent oncogene that is also significantly amplified in ovarian and breast cancer. GAB2 overexpression activates the phosphatidylinositol 3-kinase (PI3K) pathway and confers sensitivity to PI3K pathway inhibition. These results credential GAB2 as a potent oncogene in ovarian cancer and emphasize the importance of PI3K signaling in this cancer.

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the 11q13‐q14 amplicon: Clinicopathological correlations and potential drivers

Wilkerson

Reis‐Filho

2012

Genes Chromosomes & Cancer

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Amplification at 11q13-q14 is a common event in cancers from multiple anatomical sites. This complex amplicon has multiple cores and several genes have been put forward as potential "drivers." In this review, based on the technical advancements of the last decade, which resulted in methods allowing for a deeper genomic and functional genomic characterization of amplicons and their drivers, we discuss the current definitions of amplicons and driver genes, the clinical and biological significance of the 11q13-q14 amplicon in distinct types of human cancer, its coamplification partners, and the roles of various genes located within the amplicon as potential "drivers." Finally, we appraise the available data for novel therapies targeting genes mapping to this amplicon.

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Role of Gab2 in mammary tumorigenesis and metastasis

Cited by 80 publications

References 24 publications

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

The GAB2 signaling scaffold promotes anchorage independence and drives a transcriptional response associated with metastatic progression of breast cancer

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

the 11q13‐q14 amplicon: Clinicopathological correlations and potential drivers

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