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Neve, R. M.; Lane, H. A.; Hynes, N. E.

doi:10.1023/a:1011199404516

Cited by 21 publications

(12 citation statements)

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“…Human epidermal growth factor receptor 2 (HER2) (also known as ERBb2/Neu) is frequently overexpressed and/or mutated in aggressive breast cancers (9). HER2 is the molecular target of trastuzumab (Herceptin TM ).…”

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confidence: 99%

MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

Chrestensen

Shuman

Eschenroeder

et al. 2007

Journal of Biological Chemistry

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MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.The functional role of MAP 4 kinase-interacting kinase 1 (MNK1) and MNK2 in signal transduction is one of the major unsolved problems in signal transduction (1), and only recently has a MNK1 function been shown in translation of cytokines (2). Likewise, there are still large gaps in our understanding of how MNKs are regulated by MAP kinases. Human MNK1 was cloned as a novel substrate for ERK1, and the phosphorylation site identified was Thr-334 in the C terminus (3).MNK1 and MNK2 contain a canonical Thr-Pro motif for MAPKAP kinases in the T-loop, nine residues N-terminal to the conserved APE motif. Phosphorylation of the canonical Thr-Pro motif is required for activation of the RSK C-terminal domain (4), the MSK1 C-terminal domain (5), and MAPKAP kinase 2 (6). For these MAPKAP kinases, the canonical phosphorylation is the only phosphorylation required in the T-loop. However, MNK1 and MNK2 have atypical T-loops as the DFG motif is replaced by DFD, and in the only structures available (MNK2 (7)), the MNK T-loop has out-in conformations requiring a conformational switch to coordinate with Mg 2ϩ /ATP. In the T-loop of MNKs, there is a second Thr-Pro motif, which is conserved even in Drosophila melanogaster Mnk (7). The double alanine mutant of huMNK1 is inactive (T209A/T214A), and the T-loop is phosphorylated at both sites, as assessed by Thr to Ser mutations, peptide mapping, and phosphoamino acid analyses of resolved peptides (8). The available phosphospecific antibody (Cell Signaling) was made to a proprietary phosphopeptide containing both Thr-209/Thr-214 phospho-sites. The role of the canonical Thr-214 site, in particular, has not been deconvoluted and deserves more study. We investigated regulation of MNK phosphorylation with a phosphospecific antibody we generated for the canonical Thr-214 -Pro as well as the available phospho-Mnk1 (Thr-197/202) antibody (Cell Signaling).Human epidermal growth factor receptor 2 (HER2) (also known as ERBb2/Neu) is frequently overexpressed and/or mutated in aggressive breast cancers (9). HER2 is the molecular target of trastuzumab (Hercep...

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confidence: 99%

MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

Chrestensen

Shuman

Eschenroeder

et al. 2007

Journal of Biological Chemistry

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“…Its stimulation by extracellular signals leads to the activation of downstream pathways such as mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), phospholipase C and protein kinase C, inducing signal transduction and transcription [2, 3]. As such, HER-2 gene amplification and protein overexpression are involved in the pathogenesis and progression of several human cancers, thus they are often considered as a poor prognostic factor [4-6].…”

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confidence: 99%

HER-2 inhibition in gastric and colorectal cancers: tangible achievements, novel acquisitions and future perspectives

et al. 2016

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HER-2 (ErbB-2, c-erbB2 or Her2/neu), a member of the HER-family, is directly involved in the pathogenesis and progression of several human cancers; as such, it is also often considered as a poor prognostic factor. Following the revolutionary impact of anti-HER-2 therapy in breast cancer patients, the role of HER-2 and its blockade has also been extensively evaluated in other tumor types, including gastric and colorectal adenocarcinoma. The aims of this review are to recall the important results achieved with the use of HER-2 inhibitors in both gastric and colorectal cancer, and to discuss on the updates available on the role of HER-2 as prognostic and predictive factor in these malignancies.

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“…Approximately twenty percent of all breast cancers exhibit an amplification and overexpression of the HER2 gene [ 6 ]. Overexpression of HER2 can confer a selective growth and survival advantage on cancer cells and cause a more aggressive breast cancer phenotype [ 7 ]. Elevated expression of HER2 has been associated with poor prognosis including increased metastatic burden and higher recurrence and mortality rates, diminished response to anti-hormone and doxorubicin-based chemotherapy and increased sensitivity to anthracycline- and taxane-based chemotherapy [ 8 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

The combinatorial approach of laser-captured microdissection and reverse transcription quantitative polymerase chain reaction accurately determines HER2 status in breast cancer

et al. 2016

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BackgroundHER2 expression in breast cancer correlates with increased metastatic potential, higher tumor recurrence rates and improved response to targeted therapies. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are two methods commonly used for the analysis of HER2 in the clinic. However, lack of standardization, technical variability in laboratory protocols and subjective interpretation are major problems associated with these testing procedures.MethodsHere we evaluated the applicability of reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for HER2 testing in breast cancer. We tested thirty formaldehyde-fixed and paraffin-embedded tumor samples by RT-qPCR, FISH and IHC and analysed and compared the data from the three methods.ResultsWe found that laser-captured microdissection is essential for the accurate determination of HER2 expression by RT-qPCR. When isolating RNA from total tumor tissue we obtained a significant number of false negative results. However, when using RNA from purified cancer cells the RT-qPCR data were fully consistent with FISH and IHC. In addition we provide evidence that ductal carcinomas might be further classified by the differential expression of HER3 and HER4.ConclusionsLaser-captured microdissection in combination with RT-qPCR is a precise and cost-effective diagnostic approach for HER2 testing in cancer. The PCR assay is simple, accurate and robust and can easily be implemented and standardized in clinical laboratories.

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Cited by 21 publications

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MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

HER-2 inhibition in gastric and colorectal cancers: tangible achievements, novel acquisitions and future perspectives

The combinatorial approach of laser-captured microdissection and reverse transcription quantitative polymerase chain reaction accurately determines HER2 status in breast cancer

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