{"entity":{"id":"er-signaling","kind":"pathway","name":"Oestrogen receptor signalling","aka":[],"tldr":"In hormone-positive breast cancer, oestrogen binds its receptor, which switches on genes that make the cell divide. Every endocrine therapy cuts this chain somewhere.","summary":"Aromatase converts androgens to oestradiol (in ovaries pre-menopause, fat and tumour post-menopause). Oestradiol binds ERα (ESR1), which dimerises, recruits co-activators, and drives transcription of cyclin D1, MYC, PGR, and growth factors, activating CDK4/6 and cross-talking with PI3K and HER2. Tamoxifen (SERM) competes; aromatase inhibitors deplete ligand; fulvestrant and oral SERDs degrade ER; vepdegestrant (PROTAC) degrades it via cereblon. Resistance: ESR1 ligand-binding-domain mutations (ligand-independent, ~30% after AI), cyclin D1/CDK4 amplification, PI3K activation, lineage switch.","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Estrogen_receptor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Estrogen_receptor"}],"tags":[],"related":[],"cancers":["breast-hr-positive"],"sections":[],"technologies":["endocrine-therapy","protac-degrader","cdk46-inhibitor"],"targets":["estrogen-receptor","cdk4-6","pik3ca"],"drugs":["vepdegestrant","elacestrant","palbociclib","ribociclib","abemaciclib"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"analogy":"A key (oestrogen) turns a lock (ER) that opens a gate to the division machinery. Aromatase inhibitors stop making keys, tamoxifen jams a fake key in the lock, SERDs and PROTACs remove the lock from the door, and ESR1 mutations are a lock that opens without any key.","nodes":[{"id":"andro","label":"Androgens","x":20,"y":8},{"id":"arom","label":"Aromatase","x":20,"y":25},{"id":"e2","label":"Oestradiol","x":20,"y":42},{"id":"er","label":"ERα (ESR1)","x":50,"y":42,"targetId":"estrogen-receptor"},{"id":"esr1mut","label":"ESR1 Y537S / D538G","x":80,"y":25},{"id":"coact","label":"Co-activators, FOXA1","x":80,"y":55},{"id":"ccnd1","label":"Cyclin D1, MYC, PGR","x":50,"y":65},{"id":"cdk","label":"CDK4/6","x":50,"y":82,"targetId":"cdk4-6"},{"id":"prol","label":"Proliferation","x":50,"y":97}],"edges":[{"from":"andro","to":"arom","type":"activates"},{"from":"arom","to":"e2","type":"activates"},{"from":"e2","to":"er","type":"activates"},{"from":"esr1mut","to":"er","type":"activates"},{"from":"coact","to":"er","type":"activates"},{"from":"er","to":"ccnd1","type":"activates"},{"from":"ccnd1","to":"cdk","type":"activates"},{"from":"cdk","to":"prol","type":"activates"}],"interventions":["Aromatase inhibitors (letrozole, anastrozole, exemestane) ± ovarian suppression","SERMs (tamoxifen)","SERDs: fulvestrant, elacestrant, imlunestrant, camizestrant","PROTAC degrader vepdegestrant (2026)","CDK4/6 inhibitors downstream; PI3K/AKT inhibitors for cross-talk"]},"route":"/pathways/er-signaling/","neighbours":{"cancer":[{"id":"ductal-carcinoma-in-situ","kind":"cancer","name":"Ductal carcinoma in situ (DCIS)","route":"/cancers/ductal-carcinoma-in-situ/"},{"id":"breast-hr-positive","kind":"cancer","name":"HR-positive / HER2-negative breast cancer","route":"/cancers/breast-hr-positive/"},{"id":"male-breast-cancer","kind":"cancer","name":"Male breast cancer","route":"/cancers/male-breast-cancer/"},{"id":"uterine-sarcoma","kind":"cancer","name":"Uterine sarcoma","route":"/cancers/uterine-sarcoma/"}],"technology":[{"id":"cdk46-inhibitor","kind":"technology","name":"CDK4/6 inhibitors","route":"/technologies/cdk46-inhibitor/"},{"id":"endocrine-therapy","kind":"technology","name":"Endocrine therapy (SERMs, AIs, SERDs)","route":"/technologies/endocrine-therapy/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"estrogen-receptor","kind":"target","name":"Estrogen receptor (ERα)","route":"/targets/estrogen-receptor/"},{"id":"foxa1","kind":"target","name":"FOXA1","route":"/targets/foxa1/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"}],"drug":[{"id":"abemaciclib","kind":"drug","name":"Abemaciclib","route":"/drugs/abemaciclib/"},{"id":"elacestrant","kind":"drug","name":"Elacestrant","route":"/drugs/elacestrant/"},{"id":"letrozole","kind":"drug","name":"Letrozole (and other aromatase inhibitors)","route":"/drugs/letrozole/"},{"id":"palbociclib","kind":"drug","name":"Palbociclib","route":"/drugs/palbociclib/"},{"id":"megestrol-progestins","kind":"drug","name":"Progestins (megestrol acetate, medroxyprogesterone, levonorgestrel IUD)","route":"/drugs/megestrol-progestins/"},{"id":"ribociclib","kind":"drug","name":"Ribociclib","route":"/drugs/ribociclib/"},{"id":"vepdegestrant","kind":"drug","name":"Vepdegestrant","route":"/drugs/vepdegestrant/"}],"pairing":[{"id":"cdk46-plus-endocrine","kind":"pairing","name":"CDK4/6 inhibitor + endocrine therapy","route":"/pairings/cdk46-plus-endocrine/"},{"id":"pi3k-pathway-plus-endocrine","kind":"pairing","name":"PI3K/AKT-pathway inhibitor + endocrine therapy (± CDK4/6)","route":"/pairings/pi3k-pathway-plus-endocrine/"}],"pathway":[{"id":"breast-cancer-signalling","kind":"pathway","name":"Breast cancer (KEGG map)","route":"/pathways/breast-cancer-signalling/"},{"id":"endometrial-cancer-signalling","kind":"pathway","name":"Endometrial cancer (KEGG map)","route":"/pathways/endometrial-cancer-signalling/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"cell-cycle-engine-cdks","kind":"pathway","name":"The cell-cycle engine (cyclins & CDKs)","route":"/pathways/cell-cycle-engine-cdks/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"},{"id":"tumor-dormancy","kind":"pathway","name":"Tumour dormancy","route":"/pathways/tumor-dormancy/"}],"idea":[{"id":"idea-dormancy-maintenance-therapy","kind":"idea","name":"Keep them asleep: dormancy maintenance as adjuvant therapy","route":"/ideas/idea-dormancy-maintenance-therapy/"}],"term":[{"id":"hormone-therapy","kind":"term","name":"Hormone therapy","route":"/terms/hormone-therapy/"},{"id":"signalling-pathway","kind":"term","name":"Signalling pathway","route":"/terms/signalling-pathway/"}]}}