C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu

Lengyel, Ernst; Prechtel, Dieter; Resau, James H.; Gauger, K.; Welk, Anita; Lindemann, Kristina; Salanti, Georgia; Richter, Thomas; Knudsen, Beatrice S.; Woude, George F. Vande; Harbeck, Nadia

doi:10.1002/ijc.20598

Cited by 230 publications

(231 citation statements)

References 17 publications

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“…Interestingly, a similar pattern was found for MET, in accordance with previous reports (38,45,46). c-Met is also associated with poor clinical outcome and considered as a possible marker for earlier recurrence and shorter survival in breast cancer patients (47)(48)(49). Our results support the idea that the products of these two genes may cooperate within the same subtype of breast cancers: the basal type, which consists mainly of the triple-negative breast cancers (ER, progesterone receptor, and erbB2 negative).…”

Section: Discussionsupporting

confidence: 91%

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Cazet

Lefebvre

Adriaenssens

et al. 2010

Molecular Cancer Research

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The disialoganglioside G D3 is overexpressed in ∼50% of invasive ductal breast carcinoma, and the G D3 synthase gene (ST8SIA1) displays higher expression among estrogen receptor-negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that overexpression of G D3 synthase induces the accumulation of b-and c-series gangliosides (G D3 , G D2 , and G T3 ) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in the absence of serum. Here, we show that phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways are constitutively activated in G D3 synthaseexpressing cells. Analysis of phosphorylation of tyrosine kinase receptors shows a specific c-Met constitutive activation in G D3 synthase-expressing cells, in the absence of its ligand, hepatocyte growth factor/scatter factor. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that G D3 synthase expression enhances tumor growth in severe combined immunodeficient mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results show that G D3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of the c-Met receptor.

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Section: Discussionsupporting

confidence: 91%

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

Cazet

Lefebvre

Adriaenssens

et al. 2010

Molecular Cancer Research

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“…This observation was supported by a clinical study showing that MET correlated with poor outcome independent of ERBB2 (18). To determine whether we could visualize this inverse expression pattern within a tumor, we conducted coimmunohistochemical staining of MET and ERBB2 in human breast cancer tissues.…”

Section: Met and Erbb2 Are Coexpressed In Subpopulations Of Cells In mentioning

confidence: 75%

“…Under neoplastic conditions, aberrant MET signaling can occur through MET amplification, overexpression of MET and/ or HGF, autocrine signaling, or mutational activation. MET is overexpressed in 20% to 30% of breast cancer cases and is a strong, independent predictor of poor clinical outcome (14)(15)(16)(17)(18). Previously, we discovered that mutationally activated Met is able to initiate aggressive breast carcinomas in mice, and that in humans, MET overexpression highly correlates with ER À /ERBB2 À and basal-like breast cancers (19,20).…”

Section: Introductionmentioning

confidence: 99%

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

Paulson

Linklater

Berghuis

et al. 2013

Molecular Cancer Research

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Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2 þ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET À / ERBB2 þ , MET þ /ERBB2 À , and MET þ /ERBB2 þ . In a MET þ /ERBB2 þ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2 þ breast cancers express MET and contain MET þ /ERBB2 þ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance.

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“…One example of cellular regulators involved in the phosphorylation of c-Jun in breast cancer was demonstrated to be the mitogenactivated protein kinase phosphatases (Wang et al, 2003). On the other hand, hepatocyte growth factor receptor, c-Met (Edakuni et al, 2001;Parr and Jiang, 2001;Elliott et al, 2002;Lengyel et al, 2005), and the focal adhesion kinase (FAK) regulate multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. Furthermore, high expression of FAK in breast cancer is related to activation of AKT (Schmitz et al, 2005) and to the overexpression of receptor molecules such as ErbB2/ Her2 and EGFR (Lemmon, 2003).…”

mentioning

confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu

Cited by 230 publications

References 17 publications

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

GD3 Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

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