{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T11:38:36Z","timestamp":1773920316293,"version":"3.50.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Tamoxifen is a cornerstone of endocrine therapy for estrogen receptor\u2013positive breast cancer; however, its partial estrogen agonist activity in the endometrium predisposes patients to hyperplasia and, in some cases, malignant transformation. The molecular mechanisms underlying this tissue-specific adverse effect remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed immortalized human endometrial epithelial cells to investigate the role of p53 in tamoxifen-induced proliferation. Cells were genetically manipulated to express wild-type (WT) or mutant p53 (R248Q), and ALKBH5 or REG1A was silenced or overexpressed using lentiviral constructs. A comprehensive set of molecular techniques-including quantitative reverse transcription PCR (qRT-PCR), Western blotting, chromatin immunoprecipitation (ChIP), luciferase reporter assays, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and functional proliferation assays (CCK-8 and colony formation)-was applied to dissect transcriptional and post-transcriptional regulatory mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Tamoxifen promoted the recruitment of WT p53 to the ALKBH5 promoter, transcriptionally activating this m\n                      <jats:sup>6<\/jats:sup>\n                      A RNA demethylase. ALKBH5 subsequently erased m\n                      <jats:sup>6<\/jats:sup>\n                      A modifications from REG1A mRNA, preventing YTHDF2-mediated decay and thereby stabilizing REG1A expression. Elevated REG1A protein functioned as a negative feedback regulator, attenuating tamoxifen-induced proliferation. In stark contrast, the p53 R248Q mutant, despite retaining promoter-binding capacity, suppressed ALKBH5 transcription-potentially through altered cofactor recruitment-leading to increased m\n                      <jats:sup>6<\/jats:sup>\n                      A methylation of REG1A transcripts, enhanced YTHDF2-dependent degradation, and consequently, exaggerated cellular proliferation. Loss-of-function and genetic rescue experiments established that ALKBH5 is both necessary and sufficient to regulate REG1A mRNA stability, and that REG1A serves as the critical downstream effector mediating proliferative restraint under tamoxifen treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Tamoxifen\u2019s anti-proliferative effects in endometrial epithelial cells are critically dependent on WT p53, which coordinates a protective epitranscriptomic regulatory axis. In contrast, mutant p53 disrupts this checkpoint and redirects tamoxifen signaling toward hyperproliferation. These findings establish a mechanistic link between hormonal signaling, p53 allelic status, and m\n                      <jats:sup>6<\/jats:sup>\n                      A-dependent post-transcriptional regulation. Although further\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation is required, disruption of the ALKBH5\u2013REG1A axis may contribute to heterogeneous endometrial responses to tamoxifen, thereby providing a conceptual framework for biomarker-oriented investigation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1784356","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T06:51:19Z","timestamp":1773903079000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tamoxifen differentially modulates endometrial hyperplasia via wild-type and mutant p53 regulation of the ALKBH5-REG1A axis"],"prefix":"10.3389","volume":"16","author":[{"given":"Rencheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Renhe Hospital","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Renhe Hospital","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2000.105941","article-title":"Drugs for the gynecologist to prescribe in the prevention of breast cancer: current status and future trends","volume":"182","author":"Goldstein","year":"2000","journal-title":"Am J Obstet Gynecol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2016.0181","article-title":"NCCN guidelines update: Breast cancer","volume":"14","author":"Gradishar","year":"2016","journal-title":"J Natl Compr Canc Netw"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/nejm199811263392207","article-title":"Tamoxifen in the treatment of breast cancer","volume":"339","author":"Osborne","year":"1998","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)11423-4","article-title":"Tamoxifen for early breast cancer: an overview of the randomised trials. 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