Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

Abdullah Alajati, Ilaria Guccini, Sandra Pinton, Ramon Garcia-Escudero, Tiziano Bernasocchi, Manuela Sarti, Erica Montani, Andrea Rinaldi, Filippo Montemurro, Carlo Catapano, Francesco Bertoni, Andrea Alimonti

Research output: Contribution to journalArticlepeer-review

Abstract

Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of noveltherapeutic 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 invivo, 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.

Original languageEnglish
Pages (from-to)564-576
Number of pages13
JournalCell Reports
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 28 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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