{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:51:49Z","timestamp":1792173109624,"version":"4.4.0"},"reference-count":34,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Endometrial cancer (EC) is the most common gynecological malignancy in postmenopausal women. Patients with low estrogen receptor alpha (ER\u03b1) expression frequently develop aggressive pathological subtypes and have poor prognosis. The role of estradiol (E2) in ER\u03b1\u2010low EC remains poorly understood. This study investigated the tumor\u2010promoting effects of E2 using clinical data, in vitro functional assays, and a mouse xenograft model. We found that serum E2 levels were elevated in ER\u03b1\u2010low patients, of whom 67.7% showed high tumor expression of G protein\u2010coupled estrogen receptor (GPER). High GPER expression correlated with increased E2 levels, enhanced sphingosine kinase 1 (SphK1) activity, and higher Ki67 proliferation index. In vitro, E2 promoted proliferation, migration, and invasion of HEC\u20101A cells (low ER\u03b1, high GPER). These effects were suppressed by pharmacological inhibition or siRNA knockdown of GPER or SphK1. Mechanistically, E2 activated the ERK1\/2 pathway via the GPER\/SphK1 axis, leading to upregulation of Cyclin D1, Cyclin E1, and MMP\u20109. In vivo, E2 stimulated xenograft tumor growth, an effect mitigated by inhibitors of GPER, SphK1, and ERK. Our findings demonstrate that E2 drives progression of ER\u03b1\u2010low endometrial cancer through the GPER\/SphK1 signaling pathway, revealing potential therapeutic targets for this high\u2010risk subgroup.<\/jats:p>","DOI":"10.1002\/jbt.71112","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:04:26Z","timestamp":1789920266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estradiol Promotes Tumor Progression in ER\u03b1\u2010Low Endometrial Cancer via the GPER\/SphK1 Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Xiuwen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gynecology Tianjin First Central Hospital Tianjin China"},{"name":"Tianjin Medical University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haofei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of 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