{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:09:43Z","timestamp":1785409783929,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mohamed Bin Rashid University of Medicine and Health Sciences","award":["MBRU-CM-RG2022-14"],"award-info":[{"award-number":["MBRU-CM-RG2022-14"]}]},{"award":["MBRU-CM-RG2022-14"],"award-info":[{"award-number":["MBRU-CM-RG2022-14"]}],"id":[{"id":"https:\/\/ror.org\/01xfzxq83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association, to support future prevention and therapeutics, remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. In this pilot translational study, serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to human EC cells to further assess effects on cell viability, cell cycle distribution, and downstream signaling. Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum was associated with increased EC cell viability, altered cell cycle progression and PI3K\/AKT\/mTOR signaling compared with control serum in this exploratory model. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. In silico analysis identified frequent alterations in PI3K\/AKT\/mTOR-related genes in EC, consistent with pathway-level vulnerability rather than IGF1-specific dependence. These findings suggest that PCOS serum contains factors that are associated with increased EC cell viability and altered signaling pathways with partial involvement of IGF signaling; however, these findings should be interpreted cautiously given the exploratory pooled-serum design, small subgroup sizes, and use of a single EC cell line. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made.<\/jats:p>","DOI":"10.3390\/ijms27156594","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"6594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PCOS Serum Promotes Endometrial Cancer Cell Proliferation with Partial Involvement of IGF-Associated AKT\/mTOR Signaling: A Pilot Translational Study with Exploratory Molecular Insights"],"prefix":"10.3390","volume":"27","author":[{"given":"Neha","family":"Sharma","sequence":"first","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7096-0731","authenticated-orcid":false,"given":"Mahmood","family":"Hachim","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syeda Sadaf","family":"Rizvi","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baila","family":"Samreen","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumayya","family":"Inuwa","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"},{"name":"Kings College Hospital London, Dubai Hills, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasneem","family":"AbuHajjaj","sequence":"additional","affiliation":[{"name":"Latifa Hospital, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima Ba","family":"Khamis","sequence":"additional","affiliation":[{"name":"Latifa Hospital, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Alqutami","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Han","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"},{"name":"Department of Pathology, Stritch School of Medicine, Faculty of Health Sciences, Maywood Health Sciences Campus, Loyola University Medical Center Stritch School of Medicine, Chicago, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim","family":"Elrahman","sequence":"additional","affiliation":[{"name":"Kings College Hospital London, Dubai Hills, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparna","family":"Gumma","sequence":"additional","affiliation":[{"name":"Mediclinic Parkview Hospital, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uloma","family":"Okwuosa","sequence":"additional","affiliation":[{"name":"Kings College Hospital London, Dubai Hills, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Hazari","sequence":"additional","affiliation":[{"name":"Latifa Hospital, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muna","family":"Tahlak","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Health, Dubai 505055, United Arab Emirates"},{"name":"Latifa Hospital, Dubai Health, Dubai 505055, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi G.","family":"Mirza","sequence":"additional","affiliation":[{"name":"College of Medicine, Mohammed Bin Rashid University of Medicine and Health 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(2024). Recent Advances in Endometrial Cancer Prevention, Early Diagnosis and Treatment. Cancers, 16.","DOI":"10.3390\/cancers16051028"},{"key":"ref_2","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Armanini, D., Boscaro, M., Bordin, L., and Sabbadin, C. (2022). Controversies in the Pathogenesis, Diagnosis and Treatment of PCOS: Focus on Insulin Resistance, Inflammation, and Hyperandrogenism. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084110"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e12608","DOI":"10.1097\/MD.0000000000012608","article-title":"Association between Polycystic Ovarian Syndrome and Endometrial, Ovarian, and Breast Cancer: A Population-Based Cohort Study in Taiwan","volume":"97","author":"Ding","year":"2018","journal-title":"Medicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1093\/humrep\/des042","article-title":"Evaluating the Association between Endometrial Cancer and Polycystic Ovary Syndrome","volume":"27","author":"Haoula","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3892\/ol.2023.13754","article-title":"Risk of Endometrial Cancer in Patients with Polycystic Ovarian Syndrome: A Meta-analysis","volume":"25","author":"Johnson","year":"2023","journal-title":"Oncol. Lett."},{"key":"ref_7","first-page":"36","article-title":"Reassessing Hysterectomy","volume":"95","author":"Stewart","year":"2012","journal-title":"Minn. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1002\/ijc.32514","article-title":"New Perspectives on Screening and Early Detection of Endometrial Cancer","volume":"145","author":"Costas","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1089\/jwh.2020.8918","article-title":"Summary of Current Guidelines for Cervical Cancer Screening and Management of Abnormal Test Results: 2016\u20132020","volume":"30","author":"Perkins","year":"2021","journal-title":"J. Womens Health"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1016\/S0140-6736(03)13409-5","article-title":"Polycystic Ovary Syndrome and Endometrial Carcinoma","volume":"361","author":"Hardiman","year":"2003","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1038\/s41416-021-01518-3","article-title":"Testosterone, Sex Hormone-Binding Globulin, Insulin-like Growth Factor-1 and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses","volume":"125","author":"Mullee","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.mce.2016.01.019","article-title":"Up-Regulation of Genes Involved in the Insulin Signalling Pathway (IGF1, PTEN and IGFBP1) in the Endometrium May Link Polycystic Ovarian Syndrome and Endometrial Cancer","volume":"424","author":"Shafiee","year":"2016","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4950","DOI":"10.3892\/mmr.2016.5181","article-title":"Microsatellite Polymorphism in the P1 Promoter Region of the IGF-1 Gene Is Associated with Endometrial Cancer","volume":"13","author":"Kwasniewski","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"638","DOI":"10.3109\/09513590.2013.777416","article-title":"Proteomic Biomarkers of Endometrial Cancer Risk in Women with Polycystic Ovary Syndrome: A Systematic Review and Biomarker Database Integration","volume":"29","author":"Galazis","year":"2013","journal-title":"Gynecol. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3109\/09513590.2016.1138459","article-title":"IGF-1 and IGFBP-1 in Peripheral Blood and Decidua of Early Miscarriages with Euploid Embryos: Comparison between Women with and without PCOS","volume":"32","author":"Luo","year":"2016","journal-title":"Gynecol. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1006\/gyno.1993.1134","article-title":"Mitogenic Activity of Growth Factors in the Human Endometrial Adenocarcinoma Cell Lines HEC-1-A and KLE","volume":"49","author":"Pearl","year":"1993","journal-title":"Gynecol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e268","DOI":"10.1016\/S1470-2045(13)70591-6","article-title":"Classification of Endometrial Carcinoma: More than Two Types","volume":"15","author":"Murali","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nakamura, M., Obata, T., Daikoku, T., and Fujiwara, H. (2019). The Association and Significance of P53 in Gynecologic Cancers: The Potential of Targeted Therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215482"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/molehr\/gam001","article-title":"Di PI3K\/Akt And ERK1\/2 Signalling Pathways Are Involved in Endometrial Cell Migration Induced by 17\u03b2-Estradiol and Growth Factors","volume":"13","author":"Gentilini","year":"2007","journal-title":"MHR Basic Sci. Reprod. Med."},{"key":"ref_20","first-page":"CD012214","article-title":"Metformin for Endometrial Hyperplasia","volume":"2024","author":"Shiwani","year":"2024","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Varma Shrivastav, S., Bhardwaj, A., Pathak, K.A., and Shrivastav, A. (2020). Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3): Unraveling the Role in Mediating IGF-Independent Effects Within the Cell. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.00286"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3109\/08977194.2011.614237","article-title":"Signalling Pathways of Insulin-like Growth Factors (IGFs) and IGF Binding Protein-3","volume":"29","author":"Martin","year":"2011","journal-title":"Growth Factors"},{"key":"ref_23","first-page":"1627","article-title":"Testosterone and Insulin-like Growth Factor (IGF) I Interact in Controlling IGF-Binding Protein Production in Androgen-Responsive Foreskin Fibroblasts","volume":"85","author":"Yoshizawa","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jin, Y., Sun, F., Yang, A., Yu, X., Li, Y., Liang, S., Jing, X., Wang, K., Zhang, L., and Xiao, S. (2023). Insulin-like Growth Factor Binding Protein-1 and Insulin in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1279717"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/aps.2008.8","article-title":"Insulin-like Growth Factor-1 Promotes Cell Cycle Progression via Upregulation of Cyclin D1 Expression through the Phosphatidylinositol 3-Kinase\/Nuclear Factor-\u039aB Signaling Pathway in FRTL Thyroid Cells","volume":"30","author":"Ren","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1523\/JNEUROSCI.1700-08.2009","article-title":"Insulin-like Growth Factor-1 Promotes G(1)\/S Cell Cycle Progression through Bidirectional Regulation of Cyclins and Cyclin-Dependent Kinase Inhibitors via the Phosphatidylinositol 3-Kinase\/Akt Pathway in Developing Rat Cerebral Cortex","volume":"29","author":"Tury","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1002\/glia.22387","article-title":"Insulin-like Growth Factor I Regulates G2\/M Progression through Mammalian Target of Rapamycin Signaling in Oligodendrocyte Progenitors","volume":"60","author":"Min","year":"2012","journal-title":"Glia"},{"key":"ref_28","first-page":"19","article-title":"Activation and Significance of the PI3K\/Akt Pathway in Endometrium with Polycystic Ovary Syndrome Patients","volume":"47","author":"Zhang","year":"2012","journal-title":"Zhonghua Fu Chan Ke Za Zhi"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.cell.2017.04.001","article-title":"AKT\/PKB Signaling: Navigating the Network","volume":"169","author":"Manning","year":"2017","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-MTOR Pathways: Cross-Talk and Compensation","volume":"36","author":"Mendoza","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jbior.2017.06.003","article-title":"GSK3 and Its Interactions with the PI3K\/AKT\/MTOR Signalling Network","volume":"65","author":"Hermida","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118635","DOI":"10.1016\/j.bbamcr.2019.118635","article-title":"Crosstalks of GSK3 Signaling with the MTOR Network and Effects on Targeted Therapy of Cancer","volume":"1867","author":"Evangelisti","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.gendis.2021.12.025","article-title":"Decrypting a Path Based Approach for Identifying the Interplay between PI3K and GSK3 Signaling Cascade from the Perspective of Cancer","volume":"9","author":"Das","year":"2022","journal-title":"Genes Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bcp.2013.04.022","article-title":"Activator or Inhibitor? GSK-3 as a New Drug Target","volume":"86","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1757-2215-5-38","article-title":"The Mechanism of MTOR (Mammalian Target of Rapamycin) in a Mouse Model of Polycystic Ovary Syndrome (PCOS)","volume":"5","author":"Yaba","year":"2012","journal-title":"J. Ovarian Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1159\/000464351","article-title":"Akt-MTOR Signaling Mediates Abnormalities in the Proliferation and Apoptosis of Ovarian Granulosa Cells in Patients with Polycystic Ovary Syndrome","volume":"83","author":"Song","year":"2018","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ca.23211","article-title":"The Role of MTOR in Ovarian Neoplasms, Polycystic Ovary Syndrome, and Ovarian Aging","volume":"31","author":"Liu","year":"2018","journal-title":"Clin. Anat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ygyno.2014.11.012","article-title":"Risk of Cancer among Women with Polycystic Ovary Syndrome: A Danish Cohort Study","volume":"136","author":"Gottschau","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1038\/s41591-025-03592-z","article-title":"Single-Cell Profiling of the Human Endometrium in Polycystic Ovary Syndrome","volume":"31","author":"Eriksson","year":"2025","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"825","DOI":"10.18632\/oncotarget.28513","article-title":"Transcriptomic Analysis Identifies Four Novel Receptors Potentially Linking Endometrial Cancer with Polycystic Ovary Syndrome and Generates a Transcriptomic Atlas","volume":"14","author":"Alqutami","year":"2023","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e48127","DOI":"10.2196\/48127","article-title":"Deciphering the Role of Insulin-Like Growth Factor 1 in Endometrial Cancer in Patients With Polycystic Ovary Syndrome: Protocol for a Methodological Approach Using Cell Culture Experiments","volume":"12","author":"Atiomo","year":"2023","journal-title":"JMIR Res. Protoc."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group (2004). Revised 2003 Consensus on Diagnostic Criteria and Long-Term Health Risks Related to Polycystic Ovary Syndrome (PCOS). Hum. Reprod., 19, 41\u201347.","DOI":"10.1093\/humrep\/deh098"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lazic, S.E., Clarke-Williams, C.J., and Munaf\u00f2, M.R. (2018). What Exactly Is \u2018N\u2019 in Cell Culture and Animal Experiments?. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2005282"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:42:25Z","timestamp":1784889745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":43,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156594"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156594","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}