Abstract
Abstract
Background
Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear.
Methods
Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins.
Results
We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2.
Conclusions
circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.
Funder
National Key R&D Program of China
Natural Science Foundation of China
Clinical Innovation Project of Bioland Laboratory
Sun Yat-sen memorial hospital cultivation project for clinical research
Key Projects of The National Natural Science Foundation of China
Project of The Beijing Xisike Clinical Oncology Research Foundation
Technology Development Program of Guangdong province
Project of The Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
28 articles.
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