Abstract:
Background: Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of
triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors
have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting
this role is still unknown.
Methods: The membrane function of AnxA2 was blocked by incubating cells with anti-AnxA2 antibodies. Western blotting,
immunoprecipitation, immunofluorescence, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic,
and wound-healing assays were performed in this study.
Results: We demonstrate that AnxA2 interacts with epidermal growth factor receptor (EGFR) at the cell surface and has an
important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell
surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalisation by blocking its
homodimerisation. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR-dependent PI3K-AKT and Raf-MEK-
ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and
migration.
Conclusions: These findings suggest that cell-surface AnxA2 has an important regulatory role in EGFR-mediated oncogenic
processes by keeping EGFR signalling events in an activated state. Therefore, AnxA2 could potentially be used as a therapeutic
target in triple-negative and Herceptin-resistant breast cancers.
