期刊
CELL REPORTS
卷 11, 期 4, 页码 564-576出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.03.044
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资金
- Swiss National Science Foundation (Ambizione) [PZ00P3_136612/1]
- European Society for Medical Oncology Translational Research Award
- Novartis Foundation for Biomedical Research [13A50]
- Swiss Bridge Award
- European Research Council starting grant (ERCsg) [261342]
- Fondazione Veronesi fellowship (Young Investigator Programme)
- Swiss National Science Foundation (SNF) [PZ00P3_136612] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [261342] Funding Source: European Research Council (ERC)
Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.
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