PXD065700

PXD065700 is an original dataset announced via ProteomeXchange.

Title	CB2R loss drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling
Description	Despite advances in HER2+ breast cancer treatment, resistance to anti-HER2 therapies remains a significant clinical challenge. This study investigated the role of the endocannabinoid system, specifically the HER2-CB2R heterodimer, in trastuzumab resistance mechanisms. Analysis of human breast cancer samples revealed that decreased HER2-CB2R expression following neoadjuvant treatment, primarily due to CB2R reduction, correlated with poor long-term outcomes. Using cell and animal models, we demonstrated that trastuzumab resistance is dependent on CB2R expression, as it occurs upon CB2R downregulation and is reversible through CB2R re-expression. Mechanistically, CB2R loss enables cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR dimers, reducing dependence on HER2 signaling and increasing reliance on EGFR-mediated pathways. Importantly, EGFR inhibition resensitized resistant cells to trastuzumab's antitumor effects. This work identifies a novel resistance mechanism involving CB2R-mediated receptor heterodimerization and IFN-γ signaling modulation, establishes HER2-CB2R/EGFR heterodimer status and CB2R/EGFR expression as potential predictive biomarkers, and supports dual HER2/EGFR targeting as a promising strategy to overcome trastuzumab resistance in HER2+ breast cancer patients.
HostingRepository	PRIDE
AnnounceDate	2026-05-07
AnnouncementXML	Submission_2026-05-07_03:06:06.216.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ana Montero Calle
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-02 16:35:30	ID requested
⏵ 1	2026-05-07 03:06:07	announced

10.1038/S41388-026-03814-9;

submitter keyword: Breast cancer, Immunoprecipitation,Proteomics, HER2, CB2R

Rodrigo Barderas
contact affiliation	Chronic Disease Programme (UFIEC), Instituto de Salud Carlos III, Madrid, Spain
contact email	r.barderasm@isciii.es
lab head
Ana Montero Calle
contact affiliation	Instituto de Salud Carlos III
contact email	ana.monteroc@isciii.es
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD065700

PRIDE project URI

• PRIDE
  1. PXD065700
     1. Label: PRIDE project
     2. Name: CB2R loss drives trastuzumab resistance by reorganizing HER2 dimers to evade IFN-γ and enhance EGFR signaling