O-linked mucin-type glycosylation regulates the transcriptional programme downstream of EGFR in breast cancer

ABSTRACT Aberrant mucin type O-linked glycosylation is a common occurrence in cancer. This type of O-linked glycosylation is not limited to mucins but can occur on many cell surface glycoproteins where only a small number of sites may be present. Upon EGF ligation, EGFR induces a signaling cascade but can also translocate to the nucleus where it can directly regulate gene transcription. Here we show that upon EGF binding, human breast cancer cells carrying different O-linked glycans respond by transcribing different gene expression signatures. This is not a result of changes in signal transduction but due to the differential nuclear translocation of EGFR in the two glyco-phenotypes. This is regulated by the formation of an EGFR/galectin-3/MUC1/β-catenin complex at the cell surface that is present in cells carrying short core-1-based O-glycans characteristic of tumour cells but absent in core-2-carrying cells.