# When Estrogen Signaling Refuses to Die: Receptor Rewiring, Compartmentalization, and Endocrine Plasticity in Gynecological Cancers **Authors:** Jimena P. Cabilla, María Teresa L. Pino PMC · DOI: 10.3390/ijms27041924 · International Journal of Molecular Sciences · 2026-02-17 ## TL;DR This review explores how estrogen signaling changes in gynecological cancers, showing it can both promote and suppress tumors depending on the context. ## Contribution The paper introduces estrogen receptor plasticity as a unifying concept across gynecological cancers, emphasizing dynamic signaling rather than static markers. ## Key findings - Estrogen signaling in cervical cancer persists through stromal signaling and alternative receptors despite loss of ERα. - Ovarian cancer shows oncogenic signaling due to ERβ silencing and ERα dominance, creating biological vulnerabilities. - Endometrial cancer transitions to hormone-independent growth through receptor rewiring and non-genomic pathways. ## Abstract Although estrogen signaling plays an important role in gynecological cancers, its function is highly context-dependent and often contradictory. Estrogen receptors have been associated with both tumor-promoting and tumor-suppressive effects depending on the tumor type, disease stage, and cellular environment. This review summarizes the current evidence on estrogen receptor signaling in cervical, ovarian, and endometrial cancers, focusing on receptor subtype balance, isoform diversity, cellular and subcellular localization, and epigenetic regulation. Rather than a static marker, estrogen receptor expression is revealed as a dynamic and plastic signaling network. In cervical cancer, estrogen signaling persists despite the loss of epithelial estrogen receptor α (ERα) through stromal signaling, alternative ERα isoforms, ERβ, and non-classical receptors such as G protein-coupled estrogen receptor 1 (GPER1). In ovarian cancer, epigenetic silencing of ERβ and ERα predominance drives oncogenic signaling while also creating specific biological vulnerabilities. In endometrial cancer, estrogen signaling shifts from hormone-dependent initiation to progressive oncogenic autonomy through receptor rewiring and non-genomic pathways. By integrating these mechanisms, this review highlights estrogen receptor plasticity as a unifying concept across gynecological malignancies and outlines key knowledge gaps that are relevant for future endocrine strategies. ## Linked entities - **Genes:** ESR1 (estrogen receptor 1) [NCBI Gene 2099], ESR2 (estrogen receptor 2) [NCBI Gene 2100], GPER1 (G protein-coupled estrogen receptor 1) [NCBI Gene 2852] - **Diseases:** cervical cancer (MONDO:0002974), ovarian cancer (MONDO:0005140), endometrial cancer (MONDO:0002447) ## Full-text entities - **Genes:** MMP12 (matrix metallopeptidase 12) [NCBI Gene 4321] {aka HME, ME, MME, MMP-12}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, MYBL2 (MYB proto-oncogene like 2) [NCBI Gene 4605] {aka B-MYB, BMYB}, LINC00899 (long intergenic non-protein coding RNA 899) [NCBI Gene 100271722], TPI1 (triosephosphate isomerase 1) [NCBI Gene 7167] {aka HEL-S-49, TIM, TPI, TPID}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, MRTFA (myocardin related transcription factor A) [NCBI Gene 57591] {aka BSAC, MAL, MKL, MKL1, MRTF-A}, MIR206 (microRNA 206) [NCBI Gene 406989] {aka MIRN206, miRNA206, mir-206}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, CCNA2 (cyclin A2) [NCBI Gene 890] {aka CCN1, CCNA}, MIR195 (microRNA 195) [NCBI Gene 406971] {aka MIRN195, miRNA195, mir-195}, SIX1 (SIX homeobox 1) [NCBI Gene 6495] {aka BOS3, DFNA23, TIP39}, APBB3 (amyloid beta precursor protein binding family B member 3) [NCBI Gene 10307] {aka FE65L2, SRA}, PRKCD (protein kinase C delta) [NCBI Gene 5580] {aka ALPS3, CVID9, MAY1, PKCD, nPKC-delta}, INSR (insulin receptor) [NCBI Gene 3643] {aka CD220, HHF5}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, LDHB (lactate dehydrogenase B) [NCBI Gene 3945] {aka HEL-S-281, LDH-B, LDH-H, LDHBD, TRG-5}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, HSD17B1 (hydroxysteroid 17-beta dehydrogenase 1) [NCBI Gene 3292] {aka 17-beta-HSD, 20-alpha-HSD, E2DH, EDH17B2, EDHB17, HSD17}, SNAI1 (snail family transcriptional repressor 1) [NCBI Gene 6615] {aka SLUGH2, SNA, SNAH, SNAIL, SNAIL1, dJ710H13.1}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, CDKN1A (cyclin dependent kinase inhibitor 1A) [NCBI Gene 1026] {aka CAP20, CDKN1, CIP1, MDA-6, P21, SDI1}, DNMT3B (DNA methyltransferase 3 beta) [NCBI Gene 1789] {aka FSHD4, ICF, ICF1, M.HsaIIIB}, CDKN2A (cyclin dependent kinase inhibitor 2A) [NCBI Gene 1029] {aka ARF, CAI2, CDK4I, CDKN2, CMM2, INK4}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, PTEN (phosphatase and tensin homolog) [NCBI Gene 5728] {aka 10q23del, BZS, CWS1, DEC, GLM2, MHAM}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, GPI (glucose-6-phosphate isomerase) [NCBI Gene 2821] {aka AMF, CNSHA4, GNPI, NLK, PGI, PHI}, Esr2 (estrogen receptor 2 (beta)) [NCBI Gene 13983] {aka ER[b], ERbeta, Estrb}, IRS1 (insulin receptor substrate 1) [NCBI Gene 3667] {aka HIRS-1}, Fdxr (ferredoxin reductase) [NCBI Gene 14149] {aka AR}, CDH1 (cadherin 1) [NCBI Gene 999] {aka Arc-1, BCDS1, CD324, CDHE, ECAD, LCAM}, MIR424 (microRNA 424) [NCBI Gene 494336] {aka MIR322, MIRN424, hsa-mir-424, miRNA424, mir-424}, PGK1 (phosphoglycerate kinase 1) [NCBI Gene 5230] {aka HEL-S-68p, MIG10, PGKA}, SERPINE1 (serpin family E member 1) [NCBI Gene 5054] {aka PAI, PAI-1, PAI1, PLANH1}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, MMP11 (matrix metallopeptidase 11) [NCBI Gene 4320] {aka SL-3, ST3, STMY3}, CYP19A1 (cytochrome P450 family 19 subfamily A member 1) [NCBI Gene 1588] {aka ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX}, FOXA1 (forkhead box A1) [NCBI Gene 3169] {aka HNF3A, TCF3A}, Myc (Myc proto-oncogene, bHLH transcription factor) [NCBI Gene 17869] {aka Myc2, Niard, Nird, bHLHe39}, TET1 (tet methylcytosine dioxygenase 1) [NCBI Gene 80312] {aka CXXC6, LCX, bA119F7.1}, Cdkn1a (cyclin dependent kinase inhibitor 1A) [NCBI Gene 12575] {aka CAP20, CDKI, CIP1, Cdkn1, P21, SDI1}, HMGA2 (high mobility group AT-hook 2) [NCBI Gene 8091] {aka BABL, HMGI-C, HMGIC, LIPO, SRS5, STQTL9}, CCN2 (cellular communication network factor 2) [NCBI Gene 1490] {aka CTGF, HCS24, IBP-8, IGFBP8, KMD, NOV2}, ESR1 (estrogen receptor 1) [NCBI Gene 2099] {aka ER, ESR, ESRA, ESTRR, Era, NR3A1}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, IGF1R (insulin like growth factor 1 receptor) [NCBI Gene 3480] {aka CD221, IGFIR, IGFR, JTK13}, ESR2 (estrogen receptor 2) [NCBI Gene 2100] {aka ER-BETA, ESR-BETA, ESRB, ESTRB, Erb, NR3A2}, CTCFL (CCCTC-binding factor like) [NCBI Gene 140690] {aka BORIS, CT27, CTCF-T, HMGB1L1, dJ579F20.2}, EREG (epiregulin) [NCBI Gene 2069] {aka EPR, ER, Ep}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, HOTAIR (HOX transcript antisense RNA) [NCBI Gene 100124700] {aka HOXAS, HOXC-AS4, HOXC11-AS1, NCRNA00072}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA} - **Diseases:** endometrial disease (MESH:D014591), type 2 diabetes (MESH:D003924), AH (MESH:D004714), SCC (MESH:D065309), E2 (OMIM:613382), LNM (MESH:D008207), breast and vulvar tumors (MESH:D001943), obesity (MESH:D009765), aggressiveness (MESH:D010554), Ovarian Cancer (MESH:D010051), Cervical Carcinogenesis (MESH:D063646), oncogenic (MESH:D000074723), metabolic disorders (MESH:D008659), metabolic and reproductive dysfunctions (MESH:D060737), hyperplasia (MESH:D006965), Ovarian Carcinogenesis (MESH:D010049), CSCC (MESH:D002294), SCID (MESH:D053632), serous and clear-cell carcinomas (MESH:D002292), invasive (MESH:D009361), cervical lesions (MESH:D002575), injury to (MESH:D014947), ascites (MESH:D001201), osteosarcoma (MESH:D012516), chronic low-grade inflammation (MESH:D007249), epithelial OC (MESH:D009375), hyperglycemia (MESH:D006943), metastases (MESH:D009362), hyperglycemic (MESH:D006944), EC (MESH:D016889), death (MESH:D003643), carcinogenic (MESH:D011230), CC (MESH:D002583), HSILs (MESH:D000081483), mitochondrial dysfunction (MESH:D028361), serous tumors (MESH:D018297), gynecological malignancies (MESH:D005833), infected (MESH:D007239), cardiovascular disease (MESH:D002318), immune-related disorders (MESH:D007154), CACs (MESH:D000230), resistant (MESH:D060467), uterine corpus cancer (MESH:D014594), endocrine resistance (MESH:D004700), Gynecological Cancers (MESH:D009369), endometrioid carcinoma (MESH:D018269), insulin resistance (MESH:D007333), cervical dysplasia (MESH:D002578) - **Chemicals:** pentolame (MESH:C083220), estrone (MESH:D004970), LY294002 (MESH:C085911), E4 (MESH:D004953), steroid hormones (MESH:D013256), LY500307 (MESH:C000592024), raloxifene (MESH:D020849), BPA (MESH:C006780), coumestans (MESH:C505898), prolame (MESH:C047867), PD98059 (MESH:C093973), DPN (MESH:D009243), progesterone (MESH:D011374), liquiritigenin (MESH:C083152), fulvestrant (MESH:D000077267), 5-aza-2'-deoxycytidine (MESH:D000077209), glucose (MESH:D005947), cholesterol (MESH:D002784), cAMP (MESH:D000242), calcium (MESH:D002118), MEHP (MESH:C016599), 17beta-aminoestrogens (-), cisplatin (MESH:D002945), platinum (MESH:D010984), doxorubicin (MESH:D004317), butolame (MESH:C083219), lactic acid (MESH:D019344), S-equol (MESH:D060754), lignans (MESH:D017705), tamoxifen (MESH:D013629), 17beta-estradiol (MESH:D004958), paclitaxel (MESH:D017239), isoflavones (MESH:D007529), estriol (MESH:D004964) - **Species:** Human papillomavirus 16 (serotype) [taxon 333760], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Mutations:** C-33 A - **Cell lines:** AN3-CA — Homo sapiens (Human), Acanthosis nigricans, Cancer cell line (CVCL_0028), OVCAR5 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_1628), CAOV3 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_0201), RL95-2 — Homo sapiens (Human), Endometrial adenosquamous carcinoma, Cancer cell line (CVCL_0505), OVCAR-3 — Homo sapiens (Human), High grade ovarian serous adenocarcinoma, Cancer cell line (CVCL_0465), PEO4 — Homo sapiens (Human), BRCA2 syndrome, Cancer cell line (CVCL_2690), CC — Homo sapiens (Human), Human papillomavirus-related cervical squamous cell carcinoma, Cancer cell line (CVCL_T292), PEO1 — Homo sapiens (Human), BRCA2 syndrome, Cancer cell line (CVCL_2686), MASE2 — Misgurnus anguillicaudatus (Oriental weatherloach), Spontaneously immortalized cell line (CVCL_HF45), CaSki — Homo sapiens (Human), Human papillomavirus-related cervical squamous cell carcinoma, Cancer cell line (CVCL_1100), HeLa — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0030), Ishikawa — Homo sapiens (Human), Type I endometrial adenocarcinoma, Cancer cell line (CVCL_2529), SKOV3 — Homo sapiens (Human), Ovarian serous cystadenocarcinoma, Cancer cell line (CVCL_0532), BG-1 — Homo sapiens (Human), Ovarian adenocarcinoma, Cancer cell line (CVCL_6570), OV2008 — Homo sapiens (Human), Human papillomavirus-related cervical squamous cell carcinoma, Cancer cell line (CVCL_0473), SPEC-2 — Homo sapiens (Human), Endometrial serous adenocarcinoma, Cancer cell line (CVCL_A679), OC — Homo sapiens (Human), Ovarian serous cystadenocarcinoma, Cancer cell line (CVCL_A1GZ), KLE — Homo sapiens (Human), Type II endometrial adenocarcinoma, Cancer cell line (CVCL_1329), ES2 — Homo sapiens (Human), Embryonic stem cell (CVCL_C769), MASC1 — Mus musculus (Mouse), Hybridoma (CVCL_C7RB), HUVEC — Homo sapiens (Human), Finite cell line (CVCL_3722), IGROV-1 — Homo sapiens (Human), Ovarian endometrioid adenocarcinoma, Cancer cell line (CVCL_1304), HEC-1A — Homo sapiens (Human), Type II endometrial adenocarcinoma, Cancer cell line (CVCL_0293), KGN — Homo sapiens (Human), Ovarian granulosa cell tumor, Cancer cell line (CVCL_0375), SiHa — Homo sapiens (Human), Human papillomavirus-related cervical squamous cell carcinoma, Cancer cell line (CVCL_0032) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12941015/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12941015/full.md ## References 198 references — full list in the complete paper: https://tomesphere.com/paper/PMC12941015/full.md --- Source: https://tomesphere.com/paper/PMC12941015