Fig. 2

Progesterone receptor activity in breast cancer - canonical (classical; ligand-mediated) and non-canonical (alternative; ligand-independent) pathways of PR activation. a In the classical model, progesterone binds to PR, which induces receptor dimerization, translocation to the nucleus and binding to PR specific genomic sequences i.e. progesterone responsive elements. This results in regulation of expression of PR-dependent genes, followed by PR ubiquitination and proteasomal degradation. In the non-canonical pathways (b-c), PR activation is induced by tyrosine kinases. FGFRs mediate a tumour microenvironment-originated signal (FGFs), which targets PR. b FGF2/FGFR2 signalling leads to PR co-localization with STAT5 in a nucleus of cancer cells, which stimulates transcription of PRE-containing genes. c FGF7/FGFR2-triggered signalling increases transcriptional activity of PR via RSK2-mediated PR phosphorylation at Ser294 and subsequent PR ubiquitination and degradation in proteasome. P – progesterone; PR – progesterone receptor; PRE – progesterone responsive element, Ub - ubiquitin