The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer

Daly, Roger J.; Gu, Haihua; Parmar, Jayamala; Malaney, Suzann; Lyons, Ruth J.; Kairouz, Rania; Head, Darren R.; Henshall, Susan M.; Neel, Benjamin G.; Sutherland, Robert L.

doi:10.1038/sj.onc.1205522

Cited by 94 publications

(87 citation statements)

References 33 publications

(45 reference statements)

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“…Surprisingly, we found that deletion of Gab2 in mice had a minor effect on initiation or growth of mammary tumors examined in two independent MMTV-Neu transgenic mouse lines, but severely suppressed tumor metastasis to the lung. Consistent with the literature (Daly et al, 2002;Bentires-Alj et al, 2006), Gab2 expression was elevated in tumor tissues that in normal mammary epithelial tissue in both NeuYD/Gab2 þ /À and Neu2-5/Gab2 þ /À mice. These results suggest that overexpression of Gab2 may promote or at least confer a growth advantage to Neu-induced mammary tumor cells.…”

Section: Discussionsupporting

confidence: 90%

“…Like other Gab family members, Gab2 possesses a pleckstrin homology PH domain at the N-terminus, proline-rich motifs, and multiple tyrosine residues that couple with SH2-containing molecules, in a phosphorylation-dependent manner (Liu and Rohrschneider, 2002;Gu and Neel, 2003). Elevated expression of Gab2 has been found in human primary breast cancer specimens and cell lines (Daly et al, 2002). Gab2 is tyrosine-phosphorylated following stimulation with heregulin or EGF in MCF-7 human breast cancer cells (Daly et al, 2002), and overexpression of Gab2 in MCF-10A cells increased cell proliferation and altered growth factor dependency (Brummer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Elevated expression of Gab2 has been found in human primary breast cancer specimens and cell lines (Daly et al, 2002). Gab2 is tyrosine-phosphorylated following stimulation with heregulin or EGF in MCF-7 human breast cancer cells (Daly et al, 2002), and overexpression of Gab2 in MCF-10A cells increased cell proliferation and altered growth factor dependency (Brummer et al, 2005). In transgenic mice, overexpression of Gab2 accelerated NeuNT-induced mammary tumorigenesis (Bentires-Alj et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Gab2 in mammary tumorigenesis and metastasis

Yang

Princen

et al. 2007

Oncogene

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Gab2 in mammary tumorigenesis and metastasis

Yang

Princen

et al. 2007

Oncogene

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“…34 The Gab1-SHP2 signaling axis downstream of RTKs has also been shown to be critical for growth factor-induced signaling. 35 The discovery of Gab2 36 and SHP2 16 overexpression in primary breast tumors and their cooperation in promoting HER2-induced mammary tumorigenesis in transgenic mice 37 further highlight the critical role SHP2 plays in breast cancer. In conclusion, promotion of cell transformation by SHP2 is a multifaceted process that involves, at least in part, augmentation of cell proliferation and survival and suppression of adherens junction-mediated cellcell interaction.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Agazie

2008

Cell Death Differ

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The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an essential transducer of mitogenic and cell survival signaling in the epidermal growth factor receptor (EGFR) signaling pathway. However, the role of SHP2 in aberrant EGFR and human EGFR2 (HER2) signaling and cancer, particularly in breast cancer, has not been investigated. Here, we report that SHP2 is required for mitogenic and cell survival signaling and for sustaining the transformation phenotypes of breast cancer cell lines that overexpress EGFR and HER2. Inhibition of SHP2 suppressed EGF-induced activation of the Ras-ERK and the phosphatidylinositol 3 kinase-Akt signaling pathways, abolished anchorage-independent growth, induced epithelial cell morphology and led to reversion to a normal breast epithelial phenotype. Furthermore, inhibition of SHP2 led to upregulation of E-cadherin (epithelial marker) and downregulation of fibronectin and vimentin (mesenchymal markers). These results indicate that SHP2 promotes breast cancer cell phenotypes by positively modulating mitogenic and cell survival signaling, by suppressing E-cadherin expression which is known to play a tumor suppressor role and by sustaining the mesenchymal state as evidenced by the positive impact on fibronectin and vimentin expression. Therefore, SHP2 promotes epithelial to mesenchymal transition, whereas its inhibition leads to mesenchymal to epithelial transition. On the basis of these premises, we propose that interference with SHP2 function might help treat breast cancer.

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“…Gab2 knock-out mice also have defective hematopoiesis (8). It has been reported that Gab2 plays a pivotal role in BCR/ABL-induced transformation (9) and breast cancer (10). Gab2 is one of several genes in a highly amplified locus in some breast cancers (11).…”

mentioning

confidence: 99%

Interleukin-3 (IL-3)-induced c-fos Activation Is Modulated by Gab2-Calcineurin Interaction

Pyarajan

Matejovic

Pratt

et al. 2008

Journal of Biological Chemistry

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Interleukin-3 (IL-3) regulates cell growth by affecting various processes such as cell death, survival, and proliferation. Cues from the external environment are sensed by surface receptors, and complex signaling mechanisms arise within the cells, leading to specific functional outcomes. In this study, we demonstrate that the cytokine IL-3 induces the activation of the Ca 2؉ -dependent phosphatase, calcineurin (Cn). Furthermore Cn dephosphorylates Gab2, resulting in c-fos activation and cell proliferation. We also report that there is a direct interaction between Cn and Gab2 upon IL-3 stimulation, and Akt can regulate this interaction.

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The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer

Cited by 94 publications

References 33 publications

Role of Gab2 in mammary tumorigenesis and metastasis

Role of Gab2 in mammary tumorigenesis and metastasis

Inhibition of SHP2 leads to mesenchymal to epithelial transition in breast cancer cells

Interleukin-3 (IL-3)-induced c-fos Activation Is Modulated by Gab2-Calcineurin Interaction

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