Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

FOXA2 sensitizes endometrial carcinoma to progestin-mediated conservative therapy by triggering PR transcriptional activation

Oncogene (2025)Cite this article

Subjects

Abstract

Progesterone receptor (PR) expression correlates strongly with progestin sensitivity in fertility-sparing therapy for endometrial carcinoma (EC). However, the mechanisms governing PR expression remain incompletely defined. Here, by stratifying EC patients into PR-high and PR-low groups, we observe that PR-low tumors exhibit enhanced invasion and metastasis signatures, whereas PR-high tumors display increased fatty acid metabolism. Through integrated network analysis, transcriptional correlation across multiple cohorts, and single-cell transcriptomic profiling, FOXA2 is identified as a master regulator of PR expression. Specifically, FOXA2 directly binds the PR promoter, which, in turn, transcriptionally activates PR expression and increases the sensitivity of EC cells to medroxyprogesterone acetate (MPA), an oral progestin used in clinical. Overexpression of FOXA2 markedly inhibits tumor progression, evidenced with reduced cell proliferation and migration while elevated apoptosis. Moreover, FOXA2 is critically involved in lipid metabolic modulation and the administration of Orlistat, an FDA-approval inhibitor of fatty acid synthase, elevates FOXA2 and PR expression, subsequently enhancing progestin sensitivity both in vitro and in vivo. Collectively, our findings identify FOXA2 as a key regulator in controlling PR levels in EC cells and propose the activation of FOXA2-PR axis via Orlistat treatment as a promising therapeutic strategy to improve progestin responsiveness in EC patients.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Establishment of a prognostic molecular signature in EC patients on the basis of PR status.
Fig. 2: FOXA2 transcriptionally regulates PR expression in EC.
Fig. 3: FOXA2 reprograms the transcriptional landscape and suppresses EC progression.
Fig. 4: Inhibiting fatty acid synthesis upregulates FOXA2, which in turn enhances PR expression.
Fig. 5: Orlistat enhances progestin sensitivity in endometrial cancer through FOXA2-mediated PR upregulation.
Fig. 6: Schematic summary.

Similar content being viewed by others

Data availability

The transcriptomic data from public queues used in this study can be obtained from the TCGA database and GEO database. The GEO accession numbers are GSE17025 and GSE106191. The bulk transcriptomic data from Peking University People’s Hospital are available from the corresponding author upon reasonable request.

Material availability

All unique reagents generated in this study are available from lead contact with a completed material transfer agreement.

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Lucchini SM, Esteban A, Nigra MA, Palacios AT, Alzate-Granados JP, Borla HF. Updates on conservative management of endometrial cancer in patients younger than 45 years. Gynecol Oncol. 2021;161:802–9.

    Article  PubMed  CAS  Google Scholar 

  3. Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab. 2011;22:145–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Rodolakis A, Scambia G, Planchamp F, Acien M, Di Spiezio Sardo A, Farrugia M, et al. ESGO/ESHRE/ESGE Guidelines for the fertility-sparing treatment of patients with endometrial carcinoma. Hum Reprod Open. 2023;2023:hoac057.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhou R, Lu Q, Liu G, Wang Y, Wang J. Chinese expert consensus on fertility-preserving treatment for young women with early stage well differentiated endometrial cancer. Gynecol Obstet Clin Med. 2021;1:49–53.

    Article  Google Scholar 

  6. Wang Y, Zhou R, Wang H, Liu H, Wang J. Impact of treatment duration in fertility-preserving management of endometrial cancer or atypical endometrial hyperplasia. Int J Gynecol Cancer. 2019;29:699–704.

    Article  PubMed  Google Scholar 

  7. Falcone F, Leone Roberti Maggiore U, Di Donato V, Perrone AM, Frigerio L, Bifulco G, et al. Fertility-sparing treatment for intramucous, moderately differentiated, endometrioid endometrial cancer: a Gynecologic Cancer Inter-Group (GCIG) study. J Gynecol Oncol. 2020;31:e74.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lee AJ, Yang EJ, Kim NK, Kim Y, Suh DH, Kim J, et al. Fertility-sparing hormonal treatment in patients with stage I endometrial cancer of grade 2 without myometrial invasion and grade 1-2 with superficial myometrial invasion: Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-2001). Gynecol Oncol. 2023;174:106–13.

    Article  PubMed  CAS  Google Scholar 

  9. Herrera Cappelletti E, Humann J, Torrejón R, Gambadauro P. Chances of pregnancy and live birth among women undergoing conservative management of early-stage endometrial cancer: a systematic review and meta-analysis. Hum Reprod Update. 2022;28:282–95.

    Article  PubMed  Google Scholar 

  10. Chen M, Jin Y, Li Y, Bi Y, Shan Y, Pan L. Oncologic and reproductive outcomes after fertility-sparing management with oral progestin for women with complex endometrial hyperplasia and endometrial cancer. Int J Gynaecol Obstet. 2016;132:34–38.

    Article  PubMed  Google Scholar 

  11. Ma X, Xia M, Wei L, Guo K, Sun R, Liu Y, et al. ABX-1431 inhibits the development of endometrial adenocarcinoma and reverses progesterone resistance by targeting MGLL. Cell Death Dis. 2022;13:1067.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Qiu C, Dongol S, Lv QT, Gao X, Jiang J. Sterol regulatory element-binding protein-1/fatty acid synthase involvement in proliferation inhibition and apoptosis promotion induced by progesterone in endometrial cancer. Int J Gynecol Cancer. 2013;23:1629–34.

    Article  PubMed  Google Scholar 

  13. Zhang Z, Zhang M, Zhou J, Wang D. Genome-wide CRISPR screening reveals ADCK3 as a key regulator in sensitizing endometrial carcinoma cells to MPA therapy. Br J Cancer. 2023;129:601–11.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Liu J, Zhou J, Wang Y, Xue F, Chen X, Chen G, et al. Advances in the molecular mechanisms underlying progestin resistance in endometrial cancer. Fundam Res. 2023; https://doi.org/10.1016/j.fmre.2023.07.008.

  15. Yoo JY, Kim TH, Shin JH, Marquardt RM, Müller U, Fazleabas AT, et al. Loss of MIG-6 results in endometrial progesterone resistance via ERBB2. Nat Commun. 2022;13:1101.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Nakamura M, Takakura M, Fujii R, Maida Y, Bono Y, Mizumoto Y, et al. The PRB-dependent FOXO1/IGFBP-1 axis is essential for progestin to inhibit endometrial epithelial growth. Cancer Lett. 2013;336:68–75.

    Article  PubMed  CAS  Google Scholar 

  17. Hu Q, Yu L, Chen R, Wang YL, Ji L, Zhang Y, et al. 5-aza-2’-deoxycytidine improves the sensitivity of endometrial cancer cells to progesterone therapy. Int J Gynecol Cancer. 2012;22:951–9.

    Article  PubMed  Google Scholar 

  18. Rodriguez AC, Blanchard Z, Maurer KA, Gertz J. Estrogen signaling in endometrial cancer: a key oncogenic pathway with several open questions. Horm Cancer. 2019;10:51–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Asaka S, Liu Y, Yu ZC, Rahmanto YS, Ono M, Asaka R, et al. ARID1A regulates progesterone receptor expression in early endometrial endometrioid carcinoma pathogenesis. Mod Pathol. 2023;36:100045.

    Article  PubMed  CAS  Google Scholar 

  20. Yang S, Xiao X, Jia Y, Liu X, Zhang Y, Wang X, et al. Epigenetic modification restores functional PR expression in endometrial cancer cells. Curr Pharm Des. 2014;20:1874–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Qiu M, Lange CA. MAP kinases couple multiple functions of human progesterone receptors: degradation, transcriptional synergy, and nuclear association. J Steroid Biochem Mol Biol. 2003;85:147–57.

    Article  PubMed  CAS  Google Scholar 

  22. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559.

    Article  Google Scholar 

  23. Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation. 2021;2:100141.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Zhang J, Li H, Tao W, Zhou J. GseaVis: an R Package for enhanced visualization of gene set enrichment analysis in biomedicine. Med Res. 2025;1:131–5.

    Google Scholar 

  25. Wolock SL, Lopez R, Klein AM. Scrublet: computational identification of cell doublets in single-cell transcriptomic data. Cell Syst. 2019;8:281–291.e289.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14:1083–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Varghese F, Bukhari AB, Malhotra R, De A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS One. 2014;9:e96801.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hoshida Y. Nearest template prediction: a single-sample-based flexible class prediction with confidence assessment. PLoS ONE. 2010;5:e15543.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.

    Article  PubMed  Google Scholar 

  30. Mao X, Tang X, Ye J, Xu S, Wang Y, Liu X, et al. Multi-omics profiling reveal cells with novel oncogenic cluster, TRAP1(low)/CAMSAP3(low), emerge more aggressive behavior and poor-prognosis in early-stage endometrial cancer. Mol Cancer. 2024;23:127.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen YJ, Chitre AS, et al. Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature. 2020;579:274–8.

    Article  PubMed  CAS  Google Scholar 

  32. Ren X, Liang J, Zhang Y, Jiang N, Xu Y, Qiu M, et al. Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma. Nat Commun. 2022;13:6300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Guo YE, Li Y, Cai B, He Q, Chen G, Wang M, et al. Phenotyping of immune and endometrial epithelial cells in endometrial carcinomas revealed by single-cell RNA sequencing. Aging. 2021;13:6565–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. De Falco A, Caruso F, Su XD, Iavarone A, Ceccarelli M. A variational algorithm to detect the clonal copy number substructure of tumors from scRNA-seq data. Nat Commun. 2023;14:1074.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bialecka-Florjanczyk E, Fabiszewska AU, Krzyczkowska J, Kurylowicz A. Synthetic and Natural Lipase Inhibitors. Mini Rev Med Chem. 2018;18:672–83.

    Article  PubMed  CAS  Google Scholar 

  36. Kelley DE, Kuller LH, McKolanis TM, Harper P, Mancino J, Kalhan S. Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabetes Care. 2004;27:33–40.

    Article  PubMed  CAS  Google Scholar 

  37. Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature. 2004;432:1027–32.

    Article  PubMed  CAS  Google Scholar 

  38. Wolfrum C, Besser D, Luca E, Stoffel M. Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci USA. 2003;100:11624–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Ma X, Zhao T, Yan H, Guo K, Liu Z, Wei L, et al. Fatostatin reverses progesterone resistance by inhibiting the SREBP1-NF-κB pathway in endometrial carcinoma. Cell Death Dis. 2021;12:544.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Lv M, Chen P, Bai M, Huang Y, Li L, Feng Y, et al. Progestin resistance and corresponding management of abnormal endometrial hyperplasia and endometrial carcinoma. Cancers (Basel). 2022;14:6210.

  41. Huvila J, Talve L, Carpén O, Edqvist PH, Pontén F, Grénman S, et al. Progesterone receptor negativity is an independent risk factor for relapse in patients with early stage endometrioid endometrial adenocarcinoma. Gynecol Oncol. 2013;130:463–9.

    Article  PubMed  CAS  Google Scholar 

  42. Sahoo SS, Ramanand SG, Gao Y, Abbas A, Kumar A, Cuevas IC, et al. FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity. J Clin Invest. 2022;132:e157574.

  43. Liu J, Wang Z, Zhou J, Wang J, He X, Wang J. Role of steroid receptor-associated and regulated protein in tumor progression and progesterone receptor signaling in endometrial cancer. Chin Med J. 2023;136:2576–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bo L, Wang Y, Feng Y, Zhou J, Liu Y, He Y et al. Fertility-preserving treatment of endometrial cancer and endometrial atypical hyperplasia for patients with metabolic abnormalities: challenge or opportunity? Chin Med J. https://doi.org/10.1097/CM9.0000000000003721.

  45. Wang Z, Shen J, Chen C, Wen T, Li C. FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance. Biosci Trends. 2023;17:136–47.

    Article  PubMed  CAS  Google Scholar 

  46. Nakamura K, Moore R, Negishi M, Sueyoshi T. Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem. 2007;282:9768–76.

    Article  PubMed  CAS  Google Scholar 

  47. Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008;21:507–11.

    PubMed  CAS  Google Scholar 

  48. Kumar A, Sundaram K, Teng Y, Mu J, Sriwastva MK, Zhang L, et al. Ginger nanoparticles mediated induction of Foxa2 prevents high-fat diet-induced insulin resistance. Theranostics. 2022;12:1388–403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kelleher AM, Peng W, Pru JK, Pru CA, DeMayo FJ, Spencer TE. Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proc Natl Acad Sci USA. 2017;114:E1018–e1026.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Slebe F, Rojo F, Vinaixa M, García-Rocha M, Testoni G, Guiu M, et al. FoxA and LIPG endothelial lipase control the uptake of extracellular lipids for breast cancer growth. Nat Commun. 2016;7:11199.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Ortmayr K, Dubuis S, Zampieri M. Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism. Nat Commun. 2019;10:1841.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hornisch M, Piazza I. Regulation of gene expression through protein-metabolite interactions. npj Metab Health Dis. 2025;3:7.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Saguyod SJU, Alhallak I, Simmen RCM, Velarde MC. Metformin regulation of progesterone receptor isoform-B expression in human endometrial cancer cells is glucose-dependent. Oncol Lett. 2020;20:249.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol. 2011;126:113–20.

    Article  PubMed  CAS  Google Scholar 

  55. Collins G, Mesiano S, DiFeo A. Effects of metformin on cellular proliferation and steroid hormone receptors in patient-derived, low-grade endometrial cancer cell lines. Reprod Sci. 2019;26:609–18.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82230050 and 82372621) and the Beijing Natural Science Foundation (Grant Nos. Z240014 and 7234394).

Author information

Author notes

  1. These authors contributed equally: Jie Liu, Jingyuan Ning.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Peking University People’s Hospital, Beijing, China

    Jie Liu, Yiqin Wang, Xiangjun He, Jingyi Zhou & Jianliu Wang

  2. State Key Laboratory of Common Mechanism Research for Major Diseases & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Jingyuan Ning & Donglai Wang

Authors
  1. Jie Liu
    View author publications

    Search author on:PubMed Google Scholar

  2. Jingyuan Ning
    View author publications

    Search author on:PubMed Google Scholar

  3. Yiqin Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiangjun He
    View author publications

    Search author on:PubMed Google Scholar

  5. Donglai Wang
    View author publications

    Search author on:PubMed Google Scholar

  6. Jingyi Zhou
    View author publications

    Search author on:PubMed Google Scholar

  7. Jianliu Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

JL, JZ, and JW conceived and designed the study. JL performed the experiments. JN performed the bioinformatic analyses. XH and YW provided technical assistance with new reagents/analytic tools. JL, DW, JZ, and JW analysed and interpreted the data. JL, JN, JZ, and JW wrote the manuscript.

Corresponding authors

Correspondence to Jingyi Zhou or Jianliu Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and informed consent

This research was approved by the Ethics Committees of Peking University People's Hospital (No. 2022PHB391-001). All patients provided written informed consent for study participation and the use of their surgical samples in this research

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, J., Ning, J., Wang, Y. et al. FOXA2 sensitizes endometrial carcinoma to progestin-mediated conservative therapy by triggering PR transcriptional activation. Oncogene (2025). https://doi.org/10.1038/s41388-025-03564-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-025-03564-0

Search

Advanced search

Quick links