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A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.

ABSTRACT: HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well.

SUBMITTER: El-Gamal MI

PROVIDER: S-EPMC8659013 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.

El-Gamal Mohammed I MI Mewafi Nada H NH Abdelmotteleb Nada E NE Emara Minnatullah A MA Tarazi Hamadeh H Sbenati Rawan M RM Madkour Moustafa M MM Zaraei Seyed-Omar SO Shahin Afnan I AI Anbar Hanan S HS

Molecules (Basel, Switzerland) 20211205 23

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppre ...[more]

PMID: 34885957

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Project description:IntroductionWe have previously linked HER4 expression with increased survival in breast cancer. However, other reports have associated HER4 with adverse prognostic significance. One possible explanation for the conflicting reports may be that these results are antibody dependent. The HER4 protein is enzymatically cleaved, which may alter the function of its intracellular domain (ICD). We have therefore compared the staining patterns of antibodies against its intracellular and extracellular domains using tissue microarray technology.MethodsImmunohistochemistry was performed and evaluated on tumours from 402 tamoxifen treated oestrogen receptor positive patients. The HFR1 antibody recognises the ICD of HER4 and thus recognises both the intact receptor and the cleaved ICD. The H4.77.16 clone recognises an extracellular domain of HER4 and thus detects the full length receptor only.ResultsBoth antibodies demonstrated nuclear, cytoplasmic and membranous staining. Concordance between the membrane staining patterns was high (88.44%, kappa 0.426). The HFR1 antibody, however, demonstrated generally higher levels of cytoplasmic staining (concordance 74.77%, kappa 0.351). The antibodies demonstrated very different patterns of nuclear staining. Over 60% of patients stained with the H4.77.16 had no nuclear staining whereas the vast majority showed staining with the HFR1 antibody (concordance 40.12%, kappa 0.051). Neither antibody demonstrated relationships between membranous or cytoplasmic HER4 staining and survival, although associations were seen with known poor prognostic markers. Cases with H4.77.16-determined nuclear staining had significantly poorer survival outcomes.ConclusionThe difference in antigen site may explain the different staining patterns we have seen with respect to location; with each antibody appearing to select for distinct compartments. Thus, HFR1 may select for cytoplasmic and nuclear HER4 ICD, whilst H4.77.16 selects for membranous HER4 and/or HER4 being recycled in cytoplasm or nucleus. This ability to distinguish between site and function of HER4 and its fragments is particularly important, with recent evidence highlighting the different functions of nuclear and mitochondrial HER4.

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A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.

Publications

A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors.

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