{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:50:10Z","timestamp":1780465810578,"version":"3.54.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,12,30]],"date-time":"2019-12-30T00:00:00Z","timestamp":1577664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"American Cancer Society Postdoctoral Fellowship","award":["PF-17-163-02-DDC"],"award-info":[{"award-number":["PF-17-163-02-DDC"]}]},{"DOI":"10.13039\/100000983","name":"Mary Kay Foundation","doi-asserted-by":"publisher","award":["026-16"],"award-info":[{"award-number":["026-16"]}],"id":[{"id":"10.13039\/100000983","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013401","name":"Ovarian Cancer Research Fund Alliance","doi-asserted-by":"publisher","award":["457446"],"award-info":[{"award-number":["457446"]}],"id":[{"id":"10.13039\/100013401","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Is it possible to establish a genetically engineered mouse model (GEMM) of endometriosis that mimics the natural spread of invasive endometrium?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>Endometriosis occurs in an ARID1A (AT-rich interactive domain-containing protein 1A) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutant GEMM of endometrial dysfunction following salpingectomy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>Although mouse models of endometriosis have long been established, most models rely on intraperitoneal injection of uterine fragments, steroid hormone treatments or the use of immune-compromised mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>Mice harboring the lactotransferrin-Cre (LtfCre0\/+), Arid1afl, (Gt)R26Pik3ca*H1047R and (Gt)R26mTmG alleles were subject to unilateral salpingectomies at 6\u00a0weeks of age. Control (n\u2009=\u20099), LtfCre0\/+; (Gt)R26Pik3ca*H1047R; Arid1afl\/+ (n\u2009=\u20098) and LtfCre0\/+; (Gt)R26Pik3ca*H1047R; Arid1afl\/fl (n\u2009=\u20099) were used for the study. The (Gt)R26mTmG allele was used for the purpose of fluorescent lineage tracing of endometrial epithelium. LtfCre0\/+; (Gt)R26mTmG (n\u2009=\u20093) and LtfCre0\/+; (Gt)R26Pik3ca*H1047R\/mTmG; Arid1afl\/fl (n\u2009=\u20094) were used for this purpose. Mice were followed until the endpoint of vaginal bleeding at an average time of 17\u00a0weeks of age.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>At 6\u00a0weeks of age, mice were subjected to salpingectomy surgery. Mice were followed until the time point of vaginal bleeding (average 17\u00a0weeks), or aged for 1\u00a0year in the case of control mice. At time of sacrifice, endometriotic lesions, ovaries and uterus were collected for the purpose of histochemical and immunohistochemical analyses. Samples were analyzed for markers of the endometriotic tissue and other relevant biomarkers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>Following salpingectomy, LtfCre0\/+; (Gt)R26Pik3ca*H1047R\/mTmG; Arid1afl\/fl mice developed endometriotic lesions, including lesions on the ovary, omentum and abdominal wall. Epithelial glands within lesions were negative for ARID1A and positive for phospho-S6 staining, indicating ARID1A-PIK3CA co-mutation status, and expressed EGFP (enhanced green fluorescent protein), indicating endometrial origins.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LARGE-SCALE DATA<\/jats:title>\n                  <jats:p>N\/A<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>LtfCre0\/+; (Gt)R26Pik3ca*H1047R; Arid1afl\/fl mice develop vaginal bleeding as a result of endometrial dysfunction at an average age of 17\u00a0weeks and must be sacrificed. Furthermore, while this model mimics the natural spread of endometriotic tissue directly from the uterus to the peritoneum, the data presented do not reject current hypotheses on endometriosis pathogenesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>The idea that endometriosis is the result of abnormal endometrial tissue colonizing the peritoneum via retrograde menstruation has gained widespread support over the past century. However, most models of endometriosis take for granted this possibility, relying on the surgical removal of bulk uterine tissue and subsequent transplantation into the peritoneum. Growing evidence suggests that somatic mutations in ARID1A and PIK3CA are present in the endometrial epithelium. The establishment of a GEMM which mimics the natural spread of endometrium and subsequent lesion formation supports the hypothesis that endometriosis is derived from mutant endometrial epithelium with invasive properties.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This research was supported by the American Cancer Society PF-17-163-02-DDC (M.R.W.), the Mary Kay Foundation 026-16 (R.L.C.) and the Ovarian Cancer Research Fund Alliance 457446 (R.L.C.). The authors declare no competing interests.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/dez253","type":"journal-article","created":{"date-parts":[[2019,10,28]],"date-time":"2019-10-28T20:09:51Z","timestamp":1572293391000},"page":"58-69","source":"Crossref","is-referenced-by-count":26,"title":["A mouse model of endometriosis mimicking the natural spread of invasive endometrium"],"prefix":"10.1093","volume":"35","author":[{"given":"Mike R","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne","family":"Holladay","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald L","family":"Chandler","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA"},{"name":"Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA"},{"name":"Department of Women\u2019s Health, Spectrum Health System, Grand Rapids, MI 49341, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,12,30]]},"reference":[{"key":"2021061601203182800_ref1","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1158\/0008-5472.CAN-10-0738","article-title":"Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation","volume":"71","author":"Adams","year":"2011","journal-title":"Cancer Res"},{"key":"2021061601203182800_ref2","article-title":"The clinical anatomy of endometriosis: a review","volume":"10","author":"Alimi","year":"2018","journal-title":"Cureus"},{"key":"2021061601203182800_ref3","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1056\/NEJMoa1614814","article-title":"Cancer-associated mutations in endometriosis without cancer","volume":"376","author":"Anglesio","year":"2017","journal-title":"N Engl J Med"},{"key":"2021061601203182800_ref4","first-page":"220","article-title":"Successful heterotransplantation of human endometrium in SCID mice","volume":"83","author":"Aoki","year":"1994","journal-title":"Obstet Gynecol"},{"key":"2021061601203182800_ref5","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s00404-013-3040-4","article-title":"Epithelial to mesenchymal transition (EMT) seems to be regulated differently in endometriosis and the endometrium","volume":"289","author":"Bartley","year":"2014","journal-title":"Arch Gynecol Obstet"},{"key":"2021061601203182800_ref6","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.18632\/oncotarget.2675","article-title":"Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients","volume":"6","author":"Berg","year":"2015","journal-title":"Oncotarget"},{"key":"2021061601203182800_ref7","first-page":"337","article-title":"Human uterine endometrium and endometriotic tissue transplanted into nude mice. 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