PRs are rapidly SUMOylated in response to progesterone binding. SUMOylated PR species are tenfold less active on selected gene promoters and capable of ER transrepression (by unknown mechanisms). Growth factor-induced MAPK activation leading to phosphorylation of PR Ser294 prevents PR Ser388 SUMOylation, thereby lifting SUMO-dependent repression of both PR and ER transcriptional activities. Phosphorylated and deSUMOylated PR-B drives breast cancer cell proliferation and survival.
ER: Estrogen receptor; Erb: Erythroblastic leukemia viral oncogene homolog; ERE: Estrogen response element; HDAC: Histone deacetylase; hsp: Heat-shock protein; P: Phosphorylation; Pol II: RNA polymerase II; PR: Progesterone receptor; PRE: Progesterone response element; SRC: Steroid receptor coactivator; SUMO: Small ubiquitin-related modifier.