In silico assessment of ESR1 gene expression in malignancies

The Estrogen Receptor 1 (ESR1) gene plays key roles in regulating ER-responsive genes and affects many physiological processes. This gene encodes the estrogen receptor (ERα), which is essential for cellular proliferation and differentiation and is implicated in various malignancies, including osteoporosis, colon, ovarian, endometrial, and breast cancer. Due to the association of the mutagenic form of ESR1 with many types of cancers, it is also being investigated as a potential biomarker for cancers. The bulk tissue expression of the ESR1 gene is found mainly in the tissues associated with female reproductive organs (breast, cervix tissue, fallopian tubes, uterus, and vagina). This study analyzed ESR1 expression in malignancies using in silico tools. TNMplot, TIMER2.0, GTEx, GEPIA, TCGA, etc., were used to investigate differential expression of ESR1 genes across various cancers, explore gene correlations, and assess prognostic impact and survival outcomes in patients. This study revealed that tumor tissue showed higher ESR1 expression than normal or metastatic tissues. ESR1 expression was high in all pathological stages throughout the course of the malignancy. Differential overall survival was observed among breast, cervical, uterine, and ovarian malignancies. Insights from this research could lead to the development of more effective targeted therapies, improving patient outcomes, and advancing cancer treatment strategies. This aspect of gene co-expression and linked transcription may be the subject of future molecular research.

1. Altwegg K.A., Vadlamudi R.K. Role of estrogen receptor coregulators in endocrine resistant breast cancer. Explor. Target. Antitumor. Ther. 2021; 2 (4): 385-400. https://doi.org/10.37349/etat.2021.00052

2. Anderson B.O., Ilbawi A.M., Fidarova E., Weiderpass E., Stevens L., Abdel-Wahab M., Mikkelsen B. The Global Breast Cancer Initiative: a strategic collaboration to strengthen health care for non-communicable diseases. Lancet Oncol. 2021; 22 (5): 578-581. https://doi.org/10.1016/S1470-2045(21)00071-1

3. Arumalla K.K., Haince J.F., Bux R.A., Huang G., Tappia P.S., Ramjiawan B., Ford W.R., Vaida M. Metabolomics-Based Machine Learning Models Accurately Predict Breast Cancer Estrogen Receptor Status. Int. J. Mol. Sci. 2024; 25 (23): 13029. https://doi.org/10.3390/ijms252313029

4. Bahia W., Soltani I., Haddad A., Soua A., Radhouani A., Mahdhi A., Ferchichi S. Association of genetic variants in Estrogen receptor (ESR)1 and ESR2 with susceptibility to recurrent pregnancy loss in Tunisian women: A case control study. Gene. 2020; 736: 144406. https://doi.org/10.1016/j.gene.2020.144406

5. Blakely B., Shin S., Jin K. Overview of the therapeutic strategies for ER positive breast cancer. Biochem. Pharmacol. 2023; 212: 115552. https://doi.org/10.1016/j.bcp.2023.115552

6. Chakraborty B., Byemerwa J., Krebs T., Lim F., Chang C.Y., McDonnell D.P. Estrogen Receptor Signaling in the Immune System. Endocr. Rev. 2023; 44 (1): 117-141. https://doi.org/10.1210/endrev/bnac017

7. Chhabra A., Tripathi A., Rizvi S., Tyagi R.K. Ligand-independent homo-/hetero-dimerization events of ERα and ERβ occur in the cytoplasmic compartment: Evidences from receptor dynamics in live cells. The Journal of Steroid Biochemistry and Molecular Biology. 2025; 247: 106668. https://doi.org/10.1016/j.jsbmb.2024.106668

8. Chimento A., De Luca A., Avena P., De Amicis F., Casaburi I., Sirianni R., Pezzi V. Estrogen Receptors-Mediated Apoptosis in Hormone- Dependent Cancers. Int. J. Mol. Sci. 2022; 23 (3): 1242. https://doi.org/10.3390/ijms23031242

9. Clarke R., Jones B.C., Sevigny C.M., Hilakivi- Clarke L.A., Sengupta S. Experimental models of endocrine responsive breast cancer: strengths, limitations, and use. Cancer Drug Resist. 2021; 4 (4): 762-783. https://doi.org/10.20517/cdr.2021.33

10. Clusan L., Ferrière F., Flouriot G., Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int. J. Mol. Sci. 2023; 24 (7): 6834. https://doi.org/10.3390/ijms24076834

11. Dai F., Chen G., Wang Y., Zhang L., Long Y., Yuan M., Yang D., Liu S., Cheng Y., Zhang L. Identification of candidate biomarkers correlated with the diagnosis and prognosis of cervical cancer via integrated bioinformatics analysis. OncoTargets and therapy. 2019; 12: 4517-4532. https://doi.org/10.2147/OTT.S199615

12. Englert-Golon M., Andrusiewicz M., Żbikowska A., Chmielewska M., Sajdak S., Kotwicka M. Altered Expression of ESR1, ESR2, PELP1 and c-SRC Genes Is Associated with Ovarian Cancer Manifestation. Int. J. Mol. Sci. 2021; 22 (12): 6216. https://doi.org/10.3390/ijms22126216

13. Flouriot G., Brand H., Denger S., Metivier R., Kos M., Reid G., Sonntag-Buck V., Gannon F. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J. 2000; 19 (17): 4688- 4700. https://doi.org/10.1093/emboj/19.17.4688

14. Gogola-Mruk J., Pietrus M., Piechowicz M., Milian-Ciesielska K., Głód P., Wolnicka-Glubisz A., Szpor J., Ptak A. Low androgen/progesterone or high oestrogen/androgen receptors ratio in serous ovarian cancer predicts longer survival. Reprod Biol. 2024; 24 (3): 100917. https://doi.org/10.1016/j.repbio.2024.100917

15. Honkanen T.J., Tikkanen A., Karihtala P., Mäkinen M., Väyrynen J.P., Koivunen J.P. Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer. Sci. Rep. 2019; 9 (1): 10961. https://doi.org/10.1038/s41598-019-47375-2

16. Hu C., Liu Y., Jiang S., Chen H., Xu H., Hu J., Li C., Xia H. The variable association between expression and methylation of estrogen receptors and the survival of patients with different tumors. Clin. Transl. Med. 2020; 10 (2): e49. https://doi. org/10.1002/ctm2.49

17. Ji Y., Zhang R., Han X., Zhou J. Targeting the N-terminal domain of the androgen receptor: The effective approach in therapy of CRPC. Eur. J. Med. Chem. 2023; 247: 115077. https://doi.org/10.1016/j.ejmech.2022.115077

18. Johansson Å., Schmitz D., Höglund J., Hadizadeh F., Karlsson T., Ek W.E. Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer. J. Endocr. Soc. 2022; 6 (8): bvac100. https://doi.org/10.1210/jendso/bvac100

19. Koirala N., Dey N., Aske J., De P. Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity. Int. J. Mol. Sci. 2022; 23 (12): 6547. https://doi.org/10.3390/ijms23126547

20. Langdon S.P., Herrington C.S., Hollis R.L., Gourley C. Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer. Cancers (Basel). 2020; 12 (6): 1647. https://doi.org/10.3390/cancers12061647

21. Lee N., Park M.J., Song W., Jeon K., Jeong S. Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer. Int. J. Mol. Sci. 2020; 21 (22): 8807. https://doi.org/10.3390/ijms21228807

22. Marra A., Trapani D., Ferraro E., Curigliano G. Mechanisms of Endocrine Resistance in Hormone Receptor-Positive Breast Cancer. Cancer Treat. Res. 2023; 188: 219-235. https://doi.org/10.1007/978-3-031-33602-7_9

23. Mangani S., Piperigkou Z., Koletsis N.E., Ioannou P., Karamanos N.K. Estrogen receptors and extracellular matrix: the critical interplay in cancer development and progression. FEBS J. 2025; 292 (7): 1558-1572. https://doi.org/10.1111/febs.17270

24. Miziak P., Baran M., Błaszczak E., Przybyszewska-Podstawka A., Kałafut J., Smok- Kalwat J., Dmoszyńska-Graniczka M., Kiełbus M., Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers (Basel). 2023; 15 (19): 4689. https://doi.org/10.3390/cancers15194689

25. Nagaraj G., Ma C.X. Clinical Challenges in the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: A Literature Review. Adv. Ther. 2021; 38 (1): 109-136. https://doi.org/10.1007/s12325-020-01552-2

26. Razavi P., Chang M.T., Xu G., Bandlamudi C., Ross D.S., Vasan N., Cai Y., Bielski C.M., Donoghue M.T.A., Jonsson P., Penson A., Shen R., Pareja F., Kundra R., Middha S., Cheng M.L., Zehir A., Kandoth C., Patel R., Huberman K., Smyth L.M., Jhaveri K., Modi S., Traina T.A., Dang C., Zhang W., Weigelt B., Li B.T., Ladanyi M., Hyman D.M., Schultz N., Robson M.E., Hudis C., Brogi E., Viale A., Norton L., Dickler M.N., Berger M.F., Iacobuzio-Donahue C.A., Chandarlapaty S., Scaltriti M., Reis-Filho J.S., Solit D.B., Taylor B.S., Baselga J. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018; 34 (3): 427-438. https://doi.org/10.1016/j.ccell.2018.08.008

27. Rong J., Xie X., Niu Y., Su Z. Correlation between the RNA Expression and the DNA Methylation of Estrogen Receptor Genes in Normal and Malignant Human Tissues. Curr. Issues. Mol. Biol. 2024; 46 (4): 3610-3625. https://doi.org/10.3390/cimb46040226

28. Saatci O., Huynh-Dam K.T., Sahin O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. J. Mol. Med. (Berl). 2021; 99 (12): 1691-1710. https://doi.org/10.1007/s00109-021-02136-5

29. Shen Y.T., Huang X., Zhang G., Jiang B., Li C.J., Wu Z.S. Pan-Cancer Prognostic Role and Targeting Potential of the Estrogen-Progesterone Axis. Front Oncol. 2021; 11: 636365. https://doi.org/10.3389/fonc.2021.636365

30. Tanim M.T.H., Nath S.D., Khan S.F., Khan A., Sajib A.A. Transcriptomes of cervical cancer provide novel insights into dysregulated pathways, potential therapeutic targets, and repurposed drugs. Cancer Treat. Res. Commun. 2024; 39: 100808. https://doi.org/10.1016/j.ctarc.2024.100808

31. Yuan J., Wen M., Matnuri A., Zhao S., Jian N., Shen G. The expression of lnc-CCDC170-4:1, ESR1, lncRNA SRA, and CYP19A1 in cervical squamous cell carcinoma and their relationship with the clinical characteristics. Front. Oncol. 2024; 14: 1430826. https://doi.org/10.3389/fonc.2024.1430826