Differential expression of c‐Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue

Lindemann, Kristina; Resau, James H.; Nährig, Jörg; Kort, Eric J.; Leeser, Brandon; Annecke, K; Welk, Anita; Schafer, Johanna M.; Woude, George F. Vande; Lengyel, Ernst; Harbeck, Nadia

doi:10.1111/j.1365-2559.2007.02732.x

Cited by 45 publications

(40 citation statements)

References 38 publications

(109 reference statements)

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“…Increased cell proliferation, survival, motility, and extracellular matrix degradation resulting from the pathway activation contributes to tumor growth, invasiveness, and metastasis (Parr et al, 2004). In fact, high levels of HGF and Met expression associated with invasive human breast cancer have been considered as possible indicators of earlier recurrence and shortened survival in these patients (Lindemann et al, 2007). On the contrary, HGF expression but not Met is strongly suppressed in normal breast epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

Syed

Afaq

Sarfaraz

et al. 2008

Toxicology and Applied Pharmacology

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The HGF/Met signaling pathway is deregulated in majority of cancers and is associated with poor prognosis in breast cancer. Delphinidin, present in pigmented fruits and vegetables possesses potent anti-oxidant, anti-inflammatory and anti-angiogenic properties. Here, we assessed the antiproliferative and anti-invasive effects of delphinidin on HGF-mediated responses in the immortalized MCF-10A breast cell line. Treatment of cells with delphinidin prior to exposure to exogenous HGF resulted in the inhibition of HGF-mediated (i) tyrosyl-phosphorylation and increased expression of Met receptor, (ii) phosphorylation of downstream regulators such as FAK and Src and (iii) induction of adaptor proteins including paxillin, Gab-1 and GRB-2. In addition, delphinidin treatment resulted in significant inhibition of HGF-activated (i) Ras-ERK MAPKs and (ii) PI3K/AKT/mTOR/p70S6K pathways. Delphinidin was found to repress HGF-activated NFκB transcription with a decrease in (i) phosphorylation of IKKα/β and IκBα, and (ii) activation and nuclear translocation of NFκB/p65. Inhibition of HGF-mediated membrane translocation of PKCα as well as decreased phosphorylation of STAT3 was further observed in delphinidin treated cells. Finally, decreased cell viability of Met receptor expressing breast cancer cells treated with delphinidin argues for a potential role of the agent in the prevention of HGF-mediated activation of various signaling pathways implicated in breast cancer.

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Section: Introductionmentioning

confidence: 99%

“…On the contrary, HGF expression but not Met is strongly suppressed in normal breast epithelial cells. HGF and Met are therefore candidate targets for therapeutic intervention for the treatment of breast cancer (Lindemann et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

Syed

Afaq

Sarfaraz

et al. 2008

Toxicology and Applied Pharmacology

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“…5 A and B). Tumor cores were evaluated similar to Lindemann et al (25): 0, no immunoreactivity; 1, weak immunoreactivity; 2, moderately strong immunoreactivity; 3, strong immunoreactivity. Immunohistochemistry for ER, PR, ERBB2, EGF receptor (EGFR), and CK5/6 also was performed, and subtypes were determined as described (21,26).…”

Section: Met Expression Is Enhanced In Basal Andmentioning

confidence: 99%

Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer

Graveel

DeGroot

et al. 2009

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

103

119

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Understanding the signaling pathways that drive aggressive breast cancers is critical to the development of effective therapeutics. The oncogene MET is associated with decreased survival in breast cancer, yet the role that MET plays in the various breast cancer subtypes is unclear. We describe a knockin mouse with mutationally activated Met (Met mut ) that develops a high incidence of diverse mammary tumors with basal characteristics, including metaplasia, absence of progesterone receptor and ERBB2 expression, and expression of cytokeratin 5. With gene expression and tissue microarray analysis, we show that high MET expression in human breast cancers significantly correlated with estrogen receptor negative/ERBB2 negative tumors and with basal breast cancers. Few treatment options exist for breast cancers of the basal or trastuzumab-resistant ERBB2 subtypes. We conclude from these studies that MET may play a critical role in the development of the most aggressive breast cancers and may be a rational therapeutic target.ErbB2 ͉ mouse model

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“…While in the early years after its discovery Met was thought to be downregulated or absent in breast cancer, later studies showed a clear presence of the receptor in malignant breast tissue [146][147][148]. High Met protein expression levels fluctuate in studies, varying from 22-72% [64,[149][150][151][152][153][154][155][156]. HGF is not largely studied in breast cancer, protein expression in the literature range from 46-66%, when not considering localisation [150,[155][156][157].…”

Section: Proteins Of Interest In Breast Cancer Tumoursmentioning

confidence: 99%

“…Met and EGFR are reported to be involved in aggressive disease [138,153,156,[158][159][160]. An aggressive disease is indicated if the tumour is ER-negative, HER2-positive or triple-negative, and highly proliferative (as measured by NHG or S-phase fraction).…”

Section: Genes and Proteins In Relation To Clinicopathological Characmentioning

confidence: 99%

The receptor tyrosine kinase Met and the protein tyrosinephosphatase PTPN2 in breast cancer

Veenstra¹

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This thesis aimed to explore possible prognostic and predictive biomarkers in different subtypes and study their role in breast cancer. To this aid, breast cancer tumours of pre-and post-menopausal patients enrolled in two cohorts were analysed for gene copy numbers and expression of proteins involved in cell proliferation. Gene copy numbers of receptor tyrosine kinases MET and EGFR, Met's ligand HGF, and protein tyrosine phosphatase PTPN2 were determined by droplet digital PCR or quantitative PCR in both cohorts. Met, phosphorylated Met (pMet), HGF, and PTPN2 protein expression levels were analysed with immunohistochemical staining in the pre-menopausal cohort. Moreover, the role of the aforementioned proteins was investigated in breast cancer cell lines.Amplification of MET, HGF, and EGFR in breast tissues was found to be low (5-8%). These three genes, all located on chromosome 7, were found to be strongly correlated with each other and to be associated with shortened distant recurrence-free survival. High protein expression of Met, pMet, and HGF was found in 33%, 53%, and 49% of the breast tumours. MET and EGFR were found to be more often amplified in TNBC disease, correlating with worse survival.Moreover, stromal expression of HGF was associated with shorter survival in TNBC. EGF stimulation in TNBC cell line MDA-MB-468 led to inhibited cell

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Differential expression of c‐Met, its ligand HGF/SF and HER2/neu in DCIS and adjacent normal breast tissue

Abstract: An imbalance in c-Met expression between tumour and surrounding normal tissue is associated with an aggressive DCIS phenotype. Moreover, c-Met and HGF/SF may contribute to tumour development by different means than those controlled by Her2/neu.

Cited by 45 publications

References 38 publications

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation

Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer

The receptor tyrosine kinase Met and the protein tyrosinephosphatase PTPN2 in breast cancer

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