The clinical and functional significance of c-Met in breast cancer: a review

Ho-Yen, Colan M.; Jones, J. Louise; Kermorgant, Stéphanie

doi:10.1186/s13058-015-0547-6

Cited by 150 publications

(133 citation statements)

References 89 publications

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“…Moreover, this abnormality more frequently characterized basal-like BC subtypes instead of luminal and HER2-positive tumors (80). Although few evidence is available regarding the frequency and role of MET alterations in BC, in vitro and in vivo models suggest that they are actually uncommon (81). In this regard, the analysis of a cohort of 104 patients with advanced BC identified MET mutations and amplifications in the 9% and 4.7% of patients, respectively.…”

Section: Other Tumorsmentioning

confidence: 99%

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Pilotto¹,

Gkountakos²,

Carbognin³

et al. 2017

Ann. Transl. Med.

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Abstract:The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

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Section: Other Tumorsmentioning

confidence: 99%

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Pilotto¹,

Gkountakos²,

Carbognin³

et al. 2017

Ann. Transl. Med.

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“…Besides TGFβ, MET signaling importantly contributes to cell migration and metastasis formation (Birchmeier et al ., 2003; Ho‐Yen et al ., 2015). Thus, we hypothesized that HGF could also influence cell migration in vitro .…”

Section: Resultsmentioning

confidence: 99%

“…HGF is secreted by stromal cells such as cancer‐associated fibroblast (CAF) in the tumor microenvironment (Casbas‐Hernandez et al ., 2013). Upon binding of HGF to its receptor MET, it induces the activation of downstream FAK, MAPK, and PI3K/Akt signaling (Birchmeier et al ., 2003) and thereby leads to the regulation of a wide range of cellular processes such as metastasis formation in breast cancer cells (Ho‐Yen et al ., 2015). MET expression is a prognostic factor in breast carcinoma, and high levels of MET have been shown to correlate with poor survival of patients with breast cancer (Zhao et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

et al. 2018

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Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal‐like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal‐like breast cancer cell lines, as well as in triple‐negative breast cancer tumor tissues, compared to other subtypes. Using real‐time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)‐induced and MET‐dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C‐ets‐1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1‐induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR‐128‐3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR‐128‐3p reduced MET expression and abrogated HGF‐induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF‐induced and MET‐mediated cell migration, through positive regulation of C‐ets‐1 and negative regulation of miR‐128‐3p expression in basal‐like breast cancer cell lines and in triple‐negative breast cancer tissue.

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“…Antibodies can be administered to bind to both c-Met and HGF. 97,98 In addition, many approved agents are designed to block specific signaling pathways of tumor formation, survival, proliferation, progression, dissemination, and/or angiogenesis. 99 These agents represent different pharmaceutical indexes such as potency, selectivity, pharmacokinetic (PK) properties and toxicity profiles.…”

Section: Hgf and C-met Inhibitors For Treatment Of Crcmentioning

confidence: 99%

The c-Met receptor: Implication for targeted therapies in colorectal cancer

et al. 2017

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c-Met (mesenchymal-epithelial transition factor) is a tyrosine kinase receptor activated by hepatocyte growth factor and regulates multiple biological processes, such as cell scattering, survival, and proliferation. Aberrant c-Met signaling has been implicated in a variety of cancer types, including colorectal cancer. c-Met is genetically altered through various mechanisms that is associated with colorectal cancer progression and metastasis. Especially, in colorectal cancer, preclinical evidence for the aberrant activation of the c-Met signaling exists. Accordingly, molecular targeting of c-Met receptor could be a promising strategy, in the treatment of colorectal cancer patients. Recently, it was also shown that crosstalk between c-Met and other cell surface receptors attributes to tumorigenesis and development of therapeutic resistance. Characterization of the molecular mechanisms through which c-Met crosstalks with other receptors in favor of tumor formation and progression remains to explore. This review will describe the mechanisms of aberrant c-Met signaling in colorectal cancer and discuss on additional roles for c-Met receptor through crosstalk with other tyrosine kinase receptors and cell surface proteins in colorectal cancer. Novel therapeutic approaches for c-Met pathway targeting will also be discussed.

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The clinical and functional significance of c-Met in breast cancer: a review

Cited by 150 publications

References 89 publications

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

TGFβ1 regulates HGF‐induced cell migration and hepatocyte growth factor receptor MET expression via C‐ets‐1 and miR‐128‐3p in basal‐like breast cancer

The c-Met receptor: Implication for targeted therapies in colorectal cancer

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