TISIDB

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Isoform 1: Cell membrane; Single-pass type I membrane protein. Cytoplasm, perinuclear region. Nucleus. Note=Translocation to the nucleus requires endocytosis, probably endosomal sorting and is mediated by importin beta-1/KPNB1.; SUBCELLULAR LOCATION: Isoform 2: Cytoplasm. Nucleus.; SUBCELLULAR LOCATION: Isoform 3: Cytoplasm. Nucleus.
Domain	PF00757 Furin-like cysteine rich region PF14843 Growth factor receptor domain IV PF07714 Protein tyrosine kinase PF01030 Receptor L domain
Function	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. ; FUNCTION: In the nucleus is involved in transcriptional regulation. Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter and activates its transcription. Implicated in transcriptional activation of CDKN1A; the function involves STAT3 and SRC. Involved in the transcription of rRNA genes by RNA Pol I and enhances protein synthesis and cell growth.

> Gene Ontology [ TOP ]
Biological Process	GO:0001525 angiogenesis GO:0001558 regulation of cell growth GO:0002521 leukocyte differentiation GO:0002683 negative regulation of immune system process GO:0002694 regulation of leukocyte activation GO:0002695 negative regulation of leukocyte activation GO:0006356 regulation of transcription from RNA polymerase I promoter GO:0006359 regulation of transcription from RNA polymerase III promoter GO:0006360 transcription from RNA polymerase I promoter GO:0006383 transcription from RNA polymerase III promoter GO:0006417 regulation of translation GO:0006612 protein targeting to membrane GO:0006644 phospholipid metabolic process GO:0006650 glycerophospholipid metabolic process GO:0007159 leukocyte cell-cell adhesion GO:0007162 negative regulation of cell adhesion GO:0007272 ensheathment of neurons GO:0007409 axonogenesis GO:0007411 axon guidance GO:0007422 peripheral nervous system development GO:0007507 heart development GO:0007528 neuromuscular junction development GO:0008045 motor neuron axon guidance GO:0008366 axon ensheathment GO:0010001 glial cell differentiation GO:0010608 posttranscriptional regulation of gene expression GO:0014065 phosphatidylinositol 3-kinase signaling GO:0014066 regulation of phosphatidylinositol 3-kinase signaling GO:0016049 cell growth GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0022407 regulation of cell-cell adhesion GO:0022408 negative regulation of cell-cell adhesion GO:0030098 lymphocyte differentiation GO:0030217 T cell differentiation GO:0030258 lipid modification GO:0030307 positive regulation of cell growth GO:0032386 regulation of intracellular transport GO:0032388 positive regulation of intracellular transport GO:0032886 regulation of microtubule-based process GO:0032943 mononuclear cell proliferation GO:0032944 regulation of mononuclear cell proliferation GO:0032945 negative regulation of mononuclear cell proliferation GO:0033077 T cell differentiation in thymus GO:0033079 immature T cell proliferation GO:0033080 immature T cell proliferation in thymus GO:0033081 regulation of T cell differentiation in thymus GO:0033083 regulation of immature T cell proliferation GO:0033084 regulation of immature T cell proliferation in thymus GO:0033085 negative regulation of T cell differentiation in thymus GO:0033087 negative regulation of immature T cell proliferation GO:0033088 negative regulation of immature T cell proliferation in thymus GO:0033157 regulation of intracellular protein transport GO:0033674 positive regulation of kinase activity GO:0034248 regulation of cellular amide metabolic process GO:0034250 positive regulation of cellular amide metabolic process GO:0038127 ERBB signaling pathway GO:0038128 ERBB2 signaling pathway GO:0042063 gliogenesis GO:0042098 T cell proliferation GO:0042110 T cell activation GO:0042129 regulation of T cell proliferation GO:0042130 negative regulation of T cell proliferation GO:0042552 myelination GO:0043405 regulation of MAP kinase activity GO:0043406 positive regulation of MAP kinase activity GO:0043410 positive regulation of MAPK cascade GO:0045580 regulation of T cell differentiation GO:0045581 negative regulation of T cell differentiation GO:0045619 regulation of lymphocyte differentiation GO:0045620 negative regulation of lymphocyte differentiation GO:0045727 positive regulation of translation GO:0045765 regulation of angiogenesis GO:0045785 positive regulation of cell adhesion GO:0045860 positive regulation of protein kinase activity GO:0045927 positive regulation of growth GO:0045943 positive regulation of transcription from RNA polymerase I promoter GO:0045945 positive regulation of transcription from RNA polymerase III promoter GO:0046486 glycerolipid metabolic process GO:0046488 phosphatidylinositol metabolic process GO:0046651 lymphocyte proliferation GO:0046777 protein autophosphorylation GO:0046834 lipid phosphorylation GO:0046854 phosphatidylinositol phosphorylation GO:0048015 phosphatidylinositol-mediated signaling GO:0048017 inositol lipid-mediated signaling GO:0048514 blood vessel morphogenesis GO:0048667 cell morphogenesis involved in neuron differentiation GO:0048709 oligodendrocyte differentiation GO:0050670 regulation of lymphocyte proliferation GO:0050672 negative regulation of lymphocyte proliferation GO:0050673 epithelial cell proliferation GO:0050678 regulation of epithelial cell proliferation GO:0050679 positive regulation of epithelial cell proliferation GO:0050808 synapse organization GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050866 negative regulation of cell activation GO:0050868 negative regulation of T cell activation GO:0051222 positive regulation of protein transport GO:0051249 regulation of lymphocyte activation GO:0051250 negative regulation of lymphocyte activation GO:0061564 axon development GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0070663 regulation of leukocyte proliferation GO:0070664 negative regulation of leukocyte proliferation GO:0070849 response to epidermal growth factor GO:0071364 cellular response to epidermal growth factor stimulus GO:0071593 lymphocyte aggregation GO:0071594 thymocyte aggregation GO:0071900 regulation of protein serine/threonine kinase activity GO:0071902 positive regulation of protein serine/threonine kinase activity GO:0072657 protein localization to membrane GO:0090150 establishment of protein localization to membrane GO:0090313 regulation of protein targeting to membrane GO:0090314 positive regulation of protein targeting to membrane GO:0090316 positive regulation of intracellular protein transport GO:0097485 neuron projection guidance GO:1901342 regulation of vasculature development GO:1902105 regulation of leukocyte differentiation GO:1902106 negative regulation of leukocyte differentiation GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903038 negative regulation of leukocyte cell-cell adhesion GO:1903533 regulation of protein targeting GO:1903706 regulation of hemopoiesis GO:1903707 negative regulation of hemopoiesis GO:1903829 positive regulation of cellular protein localization GO:1904951 positive regulation of establishment of protein localization GO:2000398 regulation of thymocyte aggregation GO:2000399 negative regulation of thymocyte aggregation
Molecular Function	GO:0001042 RNA polymerase I core binding GO:0004713 protein tyrosine kinase activity GO:0004714 transmembrane receptor protein tyrosine kinase activity GO:0004716 receptor signaling protein tyrosine kinase activity GO:0005057 receptor signaling protein activity GO:0005085 guanyl-nucleotide exchange factor activity GO:0005088 Ras guanyl-nucleotide exchange factor activity GO:0008022 protein C-terminus binding GO:0019199 transmembrane receptor protein kinase activity GO:0019838 growth factor binding GO:0019902 phosphatase binding GO:0019903 protein phosphatase binding GO:0035004 phosphatidylinositol 3-kinase activity GO:0043125 ErbB-3 class receptor binding GO:0043175 RNA polymerase core enzyme binding GO:0046934 phosphatidylinositol-4,5-bisphosphate 3-kinase activity GO:0046982 protein heterodimerization activity GO:0052813 phosphatidylinositol bisphosphate kinase activity GO:0070063 RNA polymerase binding
Cellular Component	GO:0010008 endosome membrane GO:0016323 basolateral plasma membrane GO:0016324 apical plasma membrane GO:0043209 myelin sheath GO:0043235 receptor complex GO:0044440 endosomal part GO:0045177 apical part of cell

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04012 ErbB signaling pathway hsa04020 Calcium signaling pathway hsa04066 HIF-1 signaling pathway hsa04510 Focal adhesion hsa04520 Adherens junction hsa04530 Tight junction
Reactome	R-HSA-170984: ARMS-mediated activation R-HSA-1280218: Adaptive Immune System R-HSA-422475: Axon guidance R-HSA-2219530: Constitutive Signaling by Aberrant PI3K in Cancer R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-2172127: DAP12 interactions R-HSA-2424491: DAP12 signaling R-HSA-1266738: Developmental Biology R-HSA-1643685: Disease R-HSA-5663202: Diseases of signal transduction R-HSA-8863795: Downregulation of ERBB2 signaling R-HSA-1358803: Downregulation of ERBB2 R-HSA-186763: Downstream signal transduction R-HSA-1168372: Downstream signaling events of B Cell Receptor (BCR) R-HSA-8847993: ERBB2 Activates PTK6 Signaling R-HSA-6785631: ERBB2 Regulates Cell Motility R-HSA-2871796: FCERI mediated MAPK activation R-HSA-2454202: Fc epsilon receptor (FCERI) signaling R-HSA-170968: Frs2-mediated activation R-HSA-180292: GAB1 signalosome R-HSA-179812: GRB2 events in EGFR signaling R-HSA-1963640: GRB2 events in ERBB2 signaling R-HSA-1306955: GRB7 events in ERBB2 signaling R-HSA-881907: Gastrin-CREB signalling pathway via PKC and MAPK R-HSA-74160: Gene Expression R-HSA-212436: Generic Transcription Pathway R-HSA-2428924: IGF1R signaling cascade R-HSA-112399: IRS-mediated signalling R-HSA-2428928: IRS-related events triggered by IGF1R R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-74751: Insulin receptor signalling cascade R-HSA-912526: Interleukin receptor SHC signaling R-HSA-451927: Interleukin-2 signaling R-HSA-512988: Interleukin-3, 5 and GM-CSF signaling R-HSA-5683057: MAPK family signaling cascades R-HSA-5684996: MAPK1/MAPK3 signaling R-HSA-375165: NCAM signaling for neurite out-growth R-HSA-187037: NGF signalling via TRKA from the plasma membrane R-HSA-199418: Negative regulation of the PI3K/AKT network R-HSA-1963642: PI3K events in ERBB2 signaling R-HSA-2219528: PI3K/AKT Signaling in Cancer R-HSA-198203: PI3K/AKT activation R-HSA-6811558: PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling R-HSA-1257604: PIP3 activates AKT signaling R-HSA-1251932: PLCG1 events in ERBB2 signaling R-HSA-169893: Prolonged ERK activation events R-HSA-5673001: RAF/MAP kinase cascade R-HSA-8853659: RET signaling R-HSA-2730905: Role of LAT2/NTAL/LAB on calcium mobilization R-HSA-180336: SHC1 events in EGFR signaling R-HSA-1250196: SHC1 events in ERBB2 signaling R-HSA-112412: SOS-mediated signalling R-HSA-400685: Sema4D in semaphorin signaling R-HSA-416572: Sema4D induced cell migration and growth-cone collapse R-HSA-373755: Semaphorin interactions R-HSA-162582: Signal Transduction R-HSA-177929: Signaling by EGFR R-HSA-1227986: Signaling by ERBB2 R-HSA-372790: Signaling by GPCR R-HSA-74752: Signaling by Insulin receptor R-HSA-449147: Signaling by Interleukins R-HSA-2586552: Signaling by Leptin R-HSA-186797: Signaling by PDGF R-HSA-8848021: Signaling by PTK6 R-HSA-1433557: Signaling by SCF-KIT R-HSA-2404192: Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) R-HSA-194138: Signaling by VEGF R-HSA-983705: Signaling by the B Cell Receptor (BCR) R-HSA-166520: Signalling by NGF R-HSA-187687: Signalling to ERKs R-HSA-167044: Signalling to RAS R-HSA-187706: Signalling to p38 via RIT and RIN R-HSA-8866910: TFAP2 (AP-2) family regulates transcription of growth factors and their receptors R-HSA-8864260: Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors R-HSA-4420097: VEGFA-VEGFR2 Pathway R-HSA-5218921: VEGFR2 mediated cell proliferation

> KEGG and Reactome Pathway

[ TOP ]

KEGG

hsa04012 ErbB signaling pathway
hsa04020 Calcium signaling pathway
hsa04066 HIF-1 signaling pathway
hsa04510 Focal adhesion
hsa04520 Adherens junction
hsa04530 Tight junction

Reactome

R-HSA-170984: ARMS-mediated activation
R-HSA-1280218: Adaptive Immune System
R-HSA-422475: Axon guidance
R-HSA-2219530: Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-1280215: Cytokine Signaling in Immune system
R-HSA-2172127: DAP12 interactions
R-HSA-2424491: DAP12 signaling
R-HSA-1266738: Developmental Biology
R-HSA-1643685: Disease
R-HSA-5663202: Diseases of signal transduction
R-HSA-8863795: Downregulation of ERBB2 signaling
R-HSA-1358803: Downregulation of ERBB2
R-HSA-186763: Downstream signal transduction
R-HSA-1168372: Downstream signaling events of B Cell Receptor (BCR)
R-HSA-8847993: ERBB2 Activates PTK6 Signaling
R-HSA-6785631: ERBB2 Regulates Cell Motility
R-HSA-2871796: FCERI mediated MAPK activation
R-HSA-2454202: Fc epsilon receptor (FCERI) signaling
R-HSA-170968: Frs2-mediated activation
R-HSA-180292: GAB1 signalosome
R-HSA-179812: GRB2 events in EGFR signaling
R-HSA-1963640: GRB2 events in ERBB2 signaling
R-HSA-1306955: GRB7 events in ERBB2 signaling
R-HSA-881907: Gastrin-CREB signalling pathway via PKC and MAPK
R-HSA-74160: Gene Expression
R-HSA-212436: Generic Transcription Pathway
R-HSA-2428924: IGF1R signaling cascade
R-HSA-112399: IRS-mediated signalling
R-HSA-2428928: IRS-related events triggered by IGF1R
R-HSA-168256: Immune System
R-HSA-168249: Innate Immune System
R-HSA-74751: Insulin receptor signalling cascade
R-HSA-912526: Interleukin receptor SHC signaling
R-HSA-451927: Interleukin-2 signaling
R-HSA-512988: Interleukin-3, 5 and GM-CSF signaling
R-HSA-5683057: MAPK family signaling cascades
R-HSA-5684996: MAPK1/MAPK3 signaling
R-HSA-375165: NCAM signaling for neurite out-growth
R-HSA-187037: NGF signalling via TRKA from the plasma membrane
R-HSA-199418: Negative regulation of the PI3K/AKT network
R-HSA-1963642: PI3K events in ERBB2 signaling
R-HSA-2219528: PI3K/AKT Signaling in Cancer
R-HSA-198203: PI3K/AKT activation
R-HSA-6811558: PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-1257604: PIP3 activates AKT signaling
R-HSA-1251932: PLCG1 events in ERBB2 signaling
R-HSA-169893: Prolonged ERK activation events
R-HSA-5673001: RAF/MAP kinase cascade
R-HSA-8853659: RET signaling
R-HSA-2730905: Role of LAT2/NTAL/LAB on calcium mobilization
R-HSA-180336: SHC1 events in EGFR signaling
R-HSA-1250196: SHC1 events in ERBB2 signaling
R-HSA-112412: SOS-mediated signalling
R-HSA-400685: Sema4D in semaphorin signaling
R-HSA-416572: Sema4D induced cell migration and growth-cone collapse
R-HSA-373755: Semaphorin interactions
R-HSA-162582: Signal Transduction
R-HSA-177929: Signaling by EGFR
R-HSA-1227986: Signaling by ERBB2
R-HSA-372790: Signaling by GPCR
R-HSA-74752: Signaling by Insulin receptor
R-HSA-449147: Signaling by Interleukins
R-HSA-2586552: Signaling by Leptin
R-HSA-186797: Signaling by PDGF
R-HSA-8848021: Signaling by PTK6
R-HSA-1433557: Signaling by SCF-KIT
R-HSA-2404192: Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
R-HSA-194138: Signaling by VEGF
R-HSA-983705: Signaling by the B Cell Receptor (BCR)
R-HSA-166520: Signalling by NGF
R-HSA-187687: Signalling to ERKs
R-HSA-167044: Signalling to RAS
R-HSA-187706: Signalling to p38 via RIT and RIN
R-HSA-8866910: TFAP2 (AP-2) family regulates transcription of growth factors and their receptors
R-HSA-8864260: Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors
R-HSA-4420097: VEGFA-VEGFR2 Pathway
R-HSA-5218921: VEGFR2 mediated cell proliferation

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between ERBB2 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

[ TOP ]

Literatures describing the relation between ERBB2 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
26729864	Melanoma	Inhibit immunity (T cell function)	Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
26606967	Breast Carcinoma	Resistant to immunotherapy	We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity.
18398507	Breast carcinoma	Inhibit immunity (T cell function); immunotherapy target	Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. Trastuzumab, an approved neu-targeted mAb that targets HER-2/neu–expressing (neu-expressing) breast cancers and exerts pleiotropic antitumor effects such as inhibiting neu signaling, suppressing angiogenesis, and inducing tumor apoptosis, with the latter mechanism predominate in patients .
18347157	Breast Carcinoma	Inhibit immunity	Administration of TUBO CRCL triggered anti-HER2/neu antibody production and delayed the progression of established tumors. This antitumor activity can be transferred through the serum isolated from TUBO CRCL-immunized animals and involved both B cells and CD4(+) T lymphocytes.
18319334	Breast Carcinoma	Inhibit immunity	Level of HER-2/neu protein expression in breast cancer may affect the development of endogenous HER-2/neu-specific immunity. Data presented here indicate that endogenous HER-2/neu-specific humoral and T-cell immunity is greater in patients with +3 protein overexpression in their tumors than in patients with lower levels of HER-2/neu expression. Overexpression of a self-tumor-associated protein is a potential mechanism by which immunogenicity is enhanced and may aid in the identification of biologically relevant proteins to target for immune-based molecular cancer therapies.
16428502	Breast carcinoma	Inhibit immunity	Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. In vitro, Her2Bi-armed ATC were examined for a range of functions after repeated stimulation with the Her2/neu-expressing breast cancer cell line SK-BR-3. These studies show that armed ATC are specific, durable, and highly functional T-cell populations in vitro.
23770212	HER2 Positive Breast Carcinoma	Inhibit immunity	An antibody-cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensure the delivery of IL-2 to the tumor microenvironment. The nanobioconjugate exhibited marked anti-tumor activity manifested by significantly longer animal survival and significantly increased anti-HER2/neu immune response in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu.
22397502	Breast Carcinoma	Inhibit immunity (T cell function); immunotherapy target	We demonstrate that DEC-HER2 fusion mAb, but not Ctrl Ig-HER2, elicits strong, broad and multifunctional CD4+ T cell immunity, CD8+ T cell responses, and humoral immunity specific for HER2 antigen.
18245551	Breast Carcinoma	Inhibit immunity	Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies.
20715101	Melanoma	Inhibit immunity (T cell function)	A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-γ mediated HLA-A2 up-regulation and improved recognition by HLA-A2-restricted CTLs in treated cells.
19856307	Breast Carcinoma	Inhibit immunity	Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo.
24992895	breast carcinoma	Inhibit immunity (T cell function); immunotherapy target	They were subgrouped as the mrTNBC group (n = 18), the luminal/human epidermal growth factor receptor 2 (HER2)-negative group (n = 41) and the HER2-positive group (n = 18), while the remaining two patients had not been investigated.
24919843	Breast Carcinoma	Inhibit immunity (T cell function); immunotherapy target	However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed.
24916698	breast carcinoma; Malignant Ovarian Neoplasm	Inhibit immunity	Basal-like and HER2-enriched tumors exhibited more BCR sequence variants in regions consistent with SHM.
24907636	breast carcinoma	Inhibit immunity	We have conducted phase I/II clinical trials vaccinating breast cancer patients with nelipepimut-S and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the adjuvant setting to prevent disease recurrence.
29672836	Colorectal Carcinoma; urothelial carcinoma; urachal adenocarcinomas	Inhibit immunity (T cell function); immunotherapy target	Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA.
29659677	Colorectal carcinoma	Inhibit immunity immunotherapy target& oncogene	While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established.
29632709	breast carcinoma	Inhibit immunity	Despite substantial clinical progress with targeted therapies, current antibody-based approaches have limited efficacy at controlling HER2/neu-positive breast cancers, especially in the absence of chemotherapies.
29628923	melanoma	Inhibit immunity	In PBMC pools, beads conjugated to recombinant antigens FRα and HER2 bound antigen-specific anti-FRα MOv18 and anti-HER2 Trastuzumab antibody-expressing cells, respectively.
29622580	breast carcinoma	Inhibit immunity	To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1).
29616191	breast carcinoma	Inhibit immunity	Furthermore, ATM sustains cancer stem cells survival by promoting the autophagic flux and ATM kinase activity is enhanced in HER2-dependent tumors.
29580807	breast carcinoma	Inhibit immunity	In this study, the AE37 (Ii-Key/HER-2/neu 776-790) peptide derived from HER2 (human epidermal growth factor receptor protein) was used as a fused peptide to the lambda phage (λF7) coat protein gpD, and the phage nanoparticles were used to induce antitumor immunogenicity in a TUBO model of breast cancer in mice.
23939024	Glioblastoma	Inhibit immunity (T/NK cell function); immunotherapy target	This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.
29181007	Breast Carcinoma	Inhibit immunity	Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models.
28855210	Breast Carcinoma	Resistant to immunotherapy	CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature.
28639285	Gastric Carcinoma	Inhibit immunity; Immunotherapy target	Human epidermal growth factor receptor-2 (HER2) is overexpressed in ∼20% of GC cases and anti-HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2-positive metastatic GC.
24480556	Breast Carcinoma	Inhibit immunity; Immunotherapy target	The monoclonal antibody trastuzumab targets the growth factor receptor HER2 and has profoundly improved the course of disease and survival of women with HER2-overexpressing breast cancer.
24448235	Pancreatic Carcinoma	Inhibit immunity (T cell function)	Because phosphorylated antigens did not optimally enhance γδ T-cell cytotoxicity, we designed bispecific antibodies that bind CD3 or Vγ9 on γδ T cells and Her2/neu (ERBB2) expressed by pancreatic tumor cells. Both antibodies enhanced γδ T-cell cytotoxicity with the Her2/Vγ9 antibody also selectively enhancing release of granzyme B and perforin.
22865781	Breast Carcinoma	Inhibit immunity	Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival.
22819865	Pancreatic Adenocarcinoma	Inhibit immunity	Intratumor injection of human CD24 and Her2/neu-specific T-bodies completely eliminated the tumors from most animals. A single administration of the Her2/neu-specific T-bodies prolonged the survival of mice with tumors in which most of the cells expressed the target antigen.
20628381	Esophageal Squamous Cell Carcinoma	Inhibit immunity	There was an inverse correlation between HER2 and MHC class I expressions in both tumour tissues and cell lines. Downregulation of HER2 with siRNA resulted in the upregulation of MHC class I expression, leading to increased CTL recognition by tumour antigen-specific CTLs. HER2-overexpressing ESCC tumour cells showed a reduced sensitivity for CTLs through the downregulation of MHC class I.
20466887	Prostate Carcinoma	Inhibit immunity	Seventy-five percent of patients developed augmented immunity to the AE37 vaccine and 65% to the unmodified AE36 peptide as detected in the IFN-gamma-based ELISPOT assay. Intracellular IFN-gamma analyses revealed that AE37 elicited both CD4(+) and CD8(+) T-cell responses. AE37 vaccine is safe and can induce HER-2/neu-specific cellular immune responses in patients with castrate-sensitive and castrate-resistant prostate cancer, thus emphasizing the potential of AE37 to target HER-2/neu for the immunotherapy of prostate cancer.
29725336	Breast Carcinoma; Pancreatic Ductal Adenocarcinoma; Ovarian Neoplasm	Inhibit immunity; Immunotherapy target	Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Our results revealed the superiority of tribody [(HER2)2xCD16] compared to trastuzumab in triggering γδ T cell and NK cell-mediated lysis of HER2-expressing tumor cells, such as PDAC, breast cancer, and autologous primary ovarian tumors.
17530017	Breast Carcinoma	Inhibit immunity; Immunotherapy target	The human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor is overexpressed in approximately 20-30% of human breast cancers, and is associated with reduced survival. The humanized monoclonal antibody trastuzumab (Herceptin) was the first HER2-targeted agent approved for clinical use in breast cancer patients.
16243821	Prostate Carcinoma	Immunotherapy target	Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients. The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence.
16157940	Breast Carcinoma	Immunotherapy target	E75 is an immunogenic peptide from the HER2/neu protein that is highly expressed in breast cancer. All patients have demonstrated clonal expansion of E75-specific CD8+T cells that lysed HER2/neu-expressing tumor cells. This HER2/neu (E75) vaccine is safe and effective in eliciting a peptide-specific immune response in vivo.
16151408	Breast Carcinoma	Inhibit immunity	In addition, the anti-HER2/neu antibody trastuzumab (Herceptin), in combination with standard adjuvant chemotherapy, has been shown to reduce relapses and prolong disease-free and overall survival in high-risk patients after definitive local therapy for breast cancer.
25116755	breast carcinoma	Inhibit immunity	Adding both cyclophosphamide and the HER2-specific mAb 7.16.4 to vaccination maximized HER2-specific CD8+ T-cell immunity and tumor-free survival in neu transgenic mice

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of ERBB2 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	Total # shRNA with >= 4-fold: 1	Resistant to T-cell proliferation
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of ERBB2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.458	0.279
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.962	0.59
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	1.505	0.205
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.76	0.102
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.773	0.797
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.738	0.84
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.091	0.833
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.061	0.967
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.23	0.898
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.05	0.976
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.077	0.974
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.266	0.134

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of ERBB2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	5.5	-1.8	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	6.8	-3.1	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	0	4.8	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	0	7.7	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	22.2	12.5	9.7	0.602
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	40	0	40	0.11
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	28.6	-28.6	0.491
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	0	5.3	0.507
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of ERBB2. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of ERBB2. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by ERBB2. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of ERBB2. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of ERBB2 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between ERBB2 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	ERBB2
Name	erb-b2 receptor tyrosine kinase 2
Aliases	HER-2; CD340; HER2; neuro/glioblastoma derived oncogene homolog; human epidermal growth factor receptor 2; N ......
Chromosomal Location	17q11.2-q12
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting ERBB2 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting ERBB2.

ID	Name	Drug Type	Targets	#Targets
DB00072	Trastuzumab	Biotech	C1QA, C1QB, C1QC, C1R, C1S, EGFR, ERBB2, FCGR1A, FCGR2A, FCGR2B, F ......	13
DB01259	Lapatinib	Small Molecule	EGFR, ERBB2	2
DB04988	IGN311	Biotech	EGFR, ERBB2	2
DB05773	Trastuzumab emtansine	Biotech	ERBB2	1
DB05944	Varlitinib	Small Molecule	EGFR, ERBB2	2
DB06021	AV-412	Small Molecule	EGFR, ERBB2	2
DB06366	Pertuzumab	Biotech	ERBB2	1
DB08916	Afatinib	Small Molecule	EGFR, ERBB2, ERBB4	3
DB11652	Tucatinib	Small Molecule	ERBB2	1
DB11973	Tesevatinib	Small Molecule	EGF, EPHB4, ERBB2	3
DB12267	Brigatinib	Small Molecule	ABL1, ALK, EGFR, ERBB2, ERBB4, FLT3, IGF1R, INSR, MET	9

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