Fig. 1

Estrogen receptor (ER) activity in breast cancer - canonical (classical; ligand-mediated) and non-canonical (alternative; ligand-independent) pathways of ER activation. a In the canonical model, estrogen binds to ER, which results in receptor dimerization, subsequent translocation to the nucleus and binding to specific genomic sequences i.e. estrogen responsive elements. Activated ER interacts with co-regulators, that modulate target genes expression. This is followed by ER ubiquitination and degradation via a 26-proteasome complex. In the non-canonical pathways (b-d), activity of ER is regulated in a ligand-independent manner by stimuli (FGFs) from the tumour microenvironment (TME). Binding of FGFs to their cognate receptors, FGFRs, induces FGFRS-triggered signalling, which targets ER. b FGF3/FGFR1-triggered signalling leads to induction of ER-FGFR1 complex formation, which binds to unknown genomic sequences and regulates expression of ER-dependent genes. c FGF10/FGFR2-activated pathway strengthens the interaction between ER and two transcription factors (NFIB and YBX1), which upon binding to ER-FOXA1 suppress ER-dependent gene expression, d FGF7/FGFR2-dependent activation of PI3K/AKT induces ER phosphorylation, enhanced ER transcriptional activity and increased ER degradation. E – estrogen; ER – estrogen receptor; ERE – estrogen responsive element; Ub - ubiquitin