Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer

Minuti, Gabriele; Cappuzzo, Federico; Duchnowska, Renata; Jassem, Jacek; Fabi, Alessandra; O’Brien, Terence J.; Mendoza, Arnulfo; Landi, Lorenza; Biernat, Wojciech; Czartoryska-Arłukowicz, Bogumiła; Jankowski, Tomasz; Zuziak, Dorota; Żok, Jolanta; Szostakiewicz, Barbara; Foszczyńska-Kłoda, Małgorzata; Tempińska-Szałach, A; Rossi, Elisa; Varella‐Garcia, Marileila

doi:10.1038/bjc.2012.335

Cited by 109 publications

(78 citation statements)

References 39 publications

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“…c-Met activates its downstream effectors of the Ras-mitogen-activated protein kinase (MAPk) and phosphatidylinositol 3-kinase (PI3k)-Akt pathways to promote the invasive growth characteristic of malignancies (35,36). Also in breast cancer, disruption of the c-Met pathway has been shown to contribute to worse prognosis (20,37) and confer resistance to endocrine therapy or trastuzumab treatment (38)(39)(40). In addition to c-Met, its ligand HGF is also suggested to be an independent prognostic parameter for breast cancer (41,42).…”

Section: Discussionmentioning

confidence: 99%

Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer

Sueta

Yamamoto

Yamamoto-Ibusuki

et al. 2015

International Journal of Oncology

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Abstract. The newly identified gene, metastasis-associated in colon cancer 1 (MACC1), is suggested to be a transcriptional regulator of c-Met, leading to cancer progression in colorectal cancer. To date however, little is known of the role of MACC1 in breast cancer. In a series of 300 breast cancer patients, we analyzed the association of MACC1 mRNA and protein expression with breast cancer survival using Cox proportional hazard models. In an in vitro study, we evaluated activities of c-Met protein after transfection with a MACC1-harboring plasmid as well as the binding ability of MACC1 to the c-Met promoter using a chromatin immunoprecipitation (ChIP) assay. In survival analyses, reduced MACC1 expression was associated with patient mortality. MACC1 expression was an independent prognostic factor in multivariate analysis. In the cell lines tested, MACC1 expression was much higher in colorectal than in breast cancer cells. After cells were transfected with MACC1, c-Met expression was not induced in MCF7 cells, whereas corresponding c-Met expression was upregulated in SW480 cells. Further, SW480 cells transfected with MACC1 showed enhanced migratory ability, whereas in MDA-MB-231 cells, transfection of MACC1 had no impact on this ability. In ChIP assay, the binding of MACC1 to the c-Met promoter was suggested in SW480 cells, but not in MCF7 cells. In conclusion, our findings provide some novel insights into the role of MACC1 in breast cancer, indicating that it plays different roles in breast and several other cancers. There is a possibility that MACC1 does not modulate the transcriptional role of c-Met signaling in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer

Sueta

Yamamoto

Yamamoto-Ibusuki

et al. 2015

International Journal of Oncology

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“…MET amplification has not been reported to be common in breast cancer, in the present study only 8% was found (Paper I) [138,139]. However, copy gain has been reported for MET in 27% HER2-positive metastatic breast cancer cases, as in the pre-and post-menopausal patients here, unrelated to subtype [140]. HGF copy gain was previously reported in 65% of the HER2-positive cases, considerably higher than the 21-27% found in all patients in the two cohorts, here [140].…”

Section: Genes Of Interest In Breast Cancer Tumourscontrasting

confidence: 48%

“…However, copy gain has been reported for MET in 27% HER2-positive metastatic breast cancer cases, as in the pre-and post-menopausal patients here, unrelated to subtype [140]. HGF copy gain was previously reported in 65% of the HER2-positive cases, considerably higher than the 21-27% found in all patients in the two cohorts, here [140]. Chromosome 7q amplification has previously been reported in breast cancer [143].…”

Section: Genes Of Interest In Breast Cancer Tumoursmentioning

confidence: 46%

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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“…In a study conducted Minuti and colleagues, high gene copy numbers of MET and HGF correlated with poor outcomes and resistance to trastuzumab in HER2-positive breast cancers (46). Shattuck and colleagues demonstrated that trastuzumab-resistant primary cell lines and primary tumors also exhibited elevated expression of MET and HGF (47).…”

Section: Erbb2-positive Malignanciesmentioning

confidence: 99%

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

Ko¹,

He²,

Gadgeel³

et al. 2017

Ann. Transl. Med.

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Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer

Cited by 109 publications

References 39 publications

Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer

Differential role of MACC1 expression and its regulation of the HGF/c-Met pathway between breast and colorectal cancer

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

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

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