Molecule Information

General Information of the Molecule (ID: Mol04318)

• Name: Receptor tyrosine-protein kinase erbB-2 (ERBB2) ,Homo sapiens
• Synonyms: Metastatic lymph node gene 19 protein; Proto-oncogene Neu; Proto-oncogene c-ErbB-2; Tyrosine kinase-type cell surface receptor HER2; p185erbB2; CD_antigen=CD340
• Molecule Type: Protein
• Gene Name: ERBB2
• Gene ID: 2064
• Sequence:
  MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNL
  ELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDN
  G DPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILWKDIFHKNNQ
  LA LTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCARCKGPLPTDCCH
  EQC AAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCV
  TACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRA
  VTSAN IQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYISA
  WPDSLP DLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLRSLRELGSGLALIHHNTH
  LCFVHTV PWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGPTQCVNCS
  QFLRGQEC VEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYK
  DPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASP
  LTSIISAVVG ILLVVVLGVVFGILIKRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQ
  AQMRILKETEL RKVKVLGSGAFGTVYKGIWIPDGENVKIPVAIKVLRENTSPKANKEIL
  DEAYVMAGVGSP YVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNWCM
  QIAKGMSYLEDVR LVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPI
  KWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPP
  ICTIDVYMIMVKCWM IDSECRPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTF
  YRSLLEDDDMGDLVDA EEYLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGL
  EPSEEEAPRSPLAPSEG AGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPS
  ETDGYVAPLTCSPQPEYV NQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVV
  KDVFAFGGAVENPEYLTPQ GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGT
  PTAENPEYLGLDVPV
• Function: Protein tyrosine kinase that is part of several cell surfacereceptor complexes, but that apparently needs a coreceptor for ligandbinding. Essential component of a neuregulin-receptor complex, althoughneuregulins do not interact with it alone. GP30 is a potential ligandfor this receptor. Regulates outgrowth and stabilization of peripheralmicrotubules . Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1signaling pathway elicits the phosphorylation and thus the inhibitionof GSK3B at cell membrane. This prevents the phosphorylation of APC andCLASP2, allowing its association with the cell membrane. In turn,membrane-bound APC allows the localization of MACF1 to the cellmembrane, which is required for microtubule capture and stabilization.{ECO:0000305}.; In the nucleus is involved in transcriptional regulation.Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoterand activates its transcription. Implicated in transcriptionalactivation of CDKN1A; the function involves STAT3 and SRC. Involved inthe transcription of rRNA genes by RNA Pol I and enhances proteinsynthesis and cell growth. {ECO:0000269|PubMed:10358079,ECO:0000269|PubMed:15380516, ECO:0000269|PubMed:21555369}.
• Uniprot ID: ERBB2_HUMAN
• Ensembl ID: ENSG0000014173614
• HGNC ID: HGNC:3430

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Fulvestrant

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Triple-negative breast cancer [ICD-11: 2C60.9] [2]

• Resistant Disease: Triple-negative breast cancer [ICD-11: 2C60.9]
• Resistant Drug: Fulvestrant
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/HER2 signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 (Ful-R) cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Mechanism Description: In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R.

Disease Class: Triple-negative breast cancer [ICD-11: 2C60.9] [2]

• Resistant Disease: Triple-negative breast cancer [ICD-11: 2C60.9]
• Resistant Drug: Fulvestrant
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/HER2 signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 (Ful-R) cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Mechanism Description: In this study, we investigated the molecular mechanism underlying the loss of ER, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ER proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R.

Lapatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [3]

• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Sensitive Drug: Lapatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: HER2 signaling pathway; Inhibition; hsa04012
• In Vivo Model: Athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: CD spectroscopy assay; SDS-PAGE assay
• Experiment for Drug Resistance: Cell viability assay; Fluorescence microscope assay
• Mechanism Description: HER2-positive breast cancer constitutes 20 % of reported cases, characterized by excessive expression of HER2 receptors, pivotal in cell signaling and growth. Immunotherapy, the established treatment, often leads to multidrug resistance and tumor recurrence. There's a critical need for an effective strategy delaying drug resistance onset and ensuring cancer cell eradication. This study aimed to develop nanoparticles using human serum albumin (HSA) coupled with vitamin E (alpha-tocopherol succinate), loaded with a tyrosine kinase inhibitor (TKI) or aromatase inhibitor (AI). Nanoparticles were formed via desolvation, where HSA(VE) conjugates self-organized into a nanoparticle structure, incorporating TKI/AI either through chemical conjugation or direct binding to HSA. Physico-chemical analyses-such as infrared spectroscopy (IR), gel permeation chromatography (GPC), UV, IR, and CD spectroscopy confirmed HSA(VE) binding and drug incorporation into nanoparticles, evaluating their drug entrapment, release efficiency. Cell viability assays and in-vitro experiments on resistant and sensitive cell lines demonstrated effective drug encapsulation and absorption over time. Both in vitro and in vivo studies demonstrated that a combination of Lapa@HSA(VE) NPs and Let@HSA(VE) NPs in the ratio 75:25 inhibited tumor development and enhanced apoptosis significantly compared to individual NP treatment and free drug. The combination NPs therapy exhibited significant efficacy even in Lapa-resistant cell lines.

References

• Ref 1: Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer. Breast Cancer Res. 2024 Jun 7;26(1):95.
• Ref 2: Loss of ERalpha involved-HER2 induction mediated by the FOXO3a signaling pathway in fulvestrant-resistant breast cancer. Biochem Biophys Res Commun. 2025 Jan;742:151056.
• Ref 3: Combination therapy of Lapatinib/Letrozole-based protein-vitamin nanoparticles to enhance the therapeutic effectiveness in drug-resistant breast cancer. Colloids Surf B Biointerfaces. 2025 Mar;247:114399.