{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T03:59:02Z","timestamp":1784606342267,"version":"3.55.0"},"reference-count":73,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (\n                    <jats:italic>TSC1<\/jats:italic>\n                    or\n                    <jats:italic>TSC2<\/jats:italic>\n                    ), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of\n                    <jats:italic>Tsc2<\/jats:italic>\n                    gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -null myometrial tumors exhibit nearly all the features of LAM, including mTORC1\/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1\/S6K signaling. Additionally, we find that MMP-2 and -9, as well as neutrophil elastase (NE), are overexpressed in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -null myometrial tumors in an estrogen-dependent fashion.\n                    <jats:italic>In vivo<\/jats:italic>\n                    fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    -null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers.\n                  <\/jats:p>","DOI":"10.1530\/erc-15-0505","type":"journal-article","created":{"date-parts":[[2016,2,15]],"date-time":"2016-02-15T21:39:11Z","timestamp":1455572351000},"page":"265-280","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":38,"title":["Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model"],"prefix":"10.1530","volume":"23","author":[{"given":"Hen","family":"Prizant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Taya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Lerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Light","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aritro","family":"Sen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Mitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen R","family":"Hammes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2016051819135698000_23.4.265.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2013.03.002"},{"key":"2016051819135698000_23.4.265.2","doi-asserted-by":"crossref","unstructured":"Benassayag C Leroy MJ Rigourd V Robert B Honore JC Mignot TM Vacher-Lavenu MC Chapron C Ferre F 1999 Estrogen receptors (ERalpha\/ERbeta) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma. American Physiological Society 276 E1112\u2013E1118.","DOI":"10.1152\/ajpendo.1999.276.6.E1112"},{"key":"2016051819135698000_23.4.265.3","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/93.5.609"},{"key":"2016051819135698000_23.4.265.4","doi-asserted-by":"publisher","DOI":"10.1053\/hupa.2003.50"},{"key":"2016051819135698000_23.4.265.5","doi-asserted-by":"publisher","DOI":"10.1016\/0020-7292(95)02619-3"},{"key":"2016051819135698000_23.4.265.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.11.6085"},{"key":"2016051819135698000_23.4.265.7","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-13-34"},{"key":"2016051819135698000_23.4.265.8","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00167413"},{"key":"2016051819135698000_23.4.265.9","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-13-0453"},{"key":"2016051819135698000_23.4.265.10","doi-asserted-by":"publisher","DOI":"10.1089\/jam.2004.17.289"},{"key":"2016051819135698000_23.4.265.11","first-page":"295","article-title":"Matrix metalloproteinases and metastatic cancer","volume":"63","author":"Cockett","year":"1998","journal-title":"Biochemical Society Symposium"},{"key":"2016051819135698000_23.4.265.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1507294112"},{"key":"2016051819135698000_23.4.265.13","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44203"},{"key":"2016051819135698000_23.4.265.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2014.02.025"},{"key":"2016051819135698000_23.4.265.15","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-1283"},{"key":"2016051819135698000_23.4.265.16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202678200"},{"key":"2016051819135698000_23.4.265.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1309110110"},{"key":"2016051819135698000_23.4.265.18","doi-asserted-by":"crossref","unstructured":"Haris M Singh A Mohammed I Ittyerah R Nath K Nanga RP Debrosse C Kogan F Cai K Poptani H et al. 2014 In vivo magnetic resonance imaging of tumor protease activity. Science Reports 4 6081. (doi:10.1038\/srep06081)","DOI":"10.1038\/srep06081"},{"key":"2016051819135698000_23.4.265.19","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00674.2006"},{"key":"2016051819135698000_23.4.265.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(97)90061-7"},{"key":"2016051819135698000_23.4.265.21","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e318235edbd"},{"key":"2016051819135698000_23.4.265.22","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-151019"},{"key":"2016051819135698000_23.4.265.23","first-page":"1568","article-title":"Rodent model of reproductive tract leiomyomata. Establishment and characterization of tumor-derived cell lines","volume":"146","author":"Howe","year":"1995","journal-title":"American Journal of Pathology"},{"key":"2016051819135698000_23.4.265.24","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3892\/ijo.10.3.623","article-title":"Expression of matrix metalloproteinases 1 and 2 genes in a possible association with metastatic abilities of human pancreatic cancer cells","volume":"10","author":"Jimi","year":"1997","journal-title":"International Journal of Oncology"},{"key":"2016051819135698000_23.4.265.25","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200208-969OC"},{"key":"2016051819135698000_23.4.265.26","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-200101000-00004"},{"key":"2016051819135698000_23.4.265.27","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000147727.78571.07"},{"key":"2016051819135698000_23.4.265.28","doi-asserted-by":"publisher","DOI":"10.2739\/kurumemedj.42.141"},{"key":"2016051819135698000_23.4.265.29","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.090525"},{"key":"2016051819135698000_23.4.265.30","doi-asserted-by":"publisher","DOI":"10.1089\/lrb.2009.0019"},{"key":"2016051819135698000_23.4.265.31","doi-asserted-by":"publisher","DOI":"10.1007\/s002920100462"},{"key":"2016051819135698000_23.4.265.32","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20118"},{"key":"2016051819135698000_23.4.265.33","unstructured":"Lesma E Chiaramonte E Ancona S Orpianesi E Di Giulio AM Gorio A 2015 Anti-EGFR antibody reduces lung nodules by inhibition of EGFR-pathway in a model of lymphangioleiomyomatosis. BioMed Research International 2015 315240. (doi:10.1155\/2015\/315240)"},{"key":"2016051819135698000_23.4.265.34","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0476OC"},{"key":"2016051819135698000_23.4.265.35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131080"},{"key":"2016051819135698000_23.4.265.36","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.115.130971"},{"key":"2016051819135698000_23.4.265.37","first-page":"717","article-title":"Expression spectra of matrix metalloproteinases in metastatic non-small cell lung cancer","volume":"12","author":"Lin","year":"2004","journal-title":"Oncology Reports"},{"key":"2016051819135698000_23.4.265.38","unstructured":"Lin P Lan X Chen F Yang Y Jin Y Wang A 2013 Reference gene selection for real-time quantitative PCR analysis of the mouse uterus in the peri-implantation period. PLoS One 8 e62462. (doi:10.1371\/journal.pone.006246)"},{"key":"2016051819135698000_23.4.265.39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-148X.2008.00518.x"},{"key":"2016051819135698000_23.4.265.40","first-page":"839","article-title":"Glycoprotein non-metastatic b (GPNMB): a metastatic mediator and emerging therapeutic target in cancer","volume":"6","author":"Maric","year":"2013","journal-title":"OncoTargets and Therapy"},{"key":"2016051819135698000_23.4.265.41","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmh019"},{"key":"2016051819135698000_23.4.265.42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.5858\/2000-124-0267-RFAOMM","article-title":"Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis","volume":"124","author":"Matsui","year":"2000","journal-title":"Archives of Pathology & Laboratory Medicine"},{"key":"2016051819135698000_23.4.265.43","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1100391"},{"key":"2016051819135698000_23.4.265.44","doi-asserted-by":"publisher","DOI":"10.1097\/01.moh.0000190113.31027.d5"},{"key":"2016051819135698000_23.4.265.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2008.07.017"},{"key":"2016051819135698000_23.4.265.46","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.v30.i4.40"},{"key":"2016051819135698000_23.4.265.47","doi-asserted-by":"publisher","DOI":"10.1590\/S1806-37132011000400003"},{"key":"2016051819135698000_23.4.265.48","doi-asserted-by":"publisher","DOI":"10.1210\/me.2013-1059"},{"key":"2016051819135698000_23.4.265.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2008.02.002"},{"key":"2016051819135698000_23.4.265.50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6557"},{"key":"2016051819135698000_23.4.265.51","doi-asserted-by":"crossref","unstructured":"Rose AA Annis MG Dong Z Pepin F Hallett M Park M Siegel PM 2010a ADAM10 releases a soluble form of the GPNMB\/Osteoactivin extracellular domain with angiogenic properties. PLoS One 5 e12093. (doi:10.1371\/journal.pone.0012093)","DOI":"10.1371\/journal.pone.0012093"},{"key":"2016051819135698000_23.4.265.52","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1611"},{"key":"2016051819135698000_23.4.265.53","doi-asserted-by":"crossref","unstructured":"Ruiz de Garibay G Herranz C Llorente A Boni J Serra-Musach J Mateo F Aguilar H Gomez-Baldo L Petit A Vidal A 2015 Lymphangioleiomyomatosis biomarkers linked to lung metastatic potential and cell stemness. PLoS One 10 e0132546. (doi:10.1371\/journal.pone.0132546)","DOI":"10.1371\/journal.pone.0132546"},{"key":"2016051819135698000_23.4.265.54","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9120(98)00045-9"},{"key":"2016051819135698000_23.4.265.55","doi-asserted-by":"publisher","DOI":"10.1378\/chest.91.5.782"},{"key":"2016051819135698000_23.4.265.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2010.06.029"},{"key":"2016051819135698000_23.4.265.57","doi-asserted-by":"publisher","DOI":"10.1183\/09059180.00002813"},{"key":"2016051819135698000_23.4.265.58","doi-asserted-by":"publisher","DOI":"10.1086\/301804"},{"key":"2016051819135698000_23.4.265.59","doi-asserted-by":"crossref","unstructured":"Sun Y Gu X Zhang E Park MA Pereira AM Wang S Morrison T Li C Blenis J Gerbaudo VH 2014 Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death & Disease 5 e1231. (doi:10.1038\/cddis.2014.204)","DOI":"10.1038\/cddis.2014.204"},{"key":"2016051819135698000_23.4.265.60","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.95.08111879"},{"key":"2016051819135698000_23.4.265.61","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-154-12-201106210-00007"},{"key":"2016051819135698000_23.4.265.62","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2008.00830.x"},{"key":"2016051819135698000_23.4.265.63","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0000000000000250"},{"key":"2016051819135698000_23.4.265.64","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-2018"},{"key":"2016051819135698000_23.4.265.65","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199909000-00004"},{"key":"2016051819135698000_23.4.265.66","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.38.26776"},{"key":"2016051819135698000_23.4.265.67","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1096\/fasebj.5.8.1850705","article-title":"Matrix metalloproteinases and their inhibitors in connective tissue remodeling","volume":"5","author":"Woessner","year":"1991","journal-title":"FASEB Journal"},{"key":"2016051819135698000_23.4.265.68","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.57.12.1085"},{"key":"2016051819135698000_23.4.265.69","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.24763"},{"key":"2016051819135698000_23.4.265.70","doi-asserted-by":"crossref","unstructured":"Yu J Astrinidis A Howard S Henske EP 2004 Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic |signaling pathways. American Journal of Physiology: Lung Cellular and Molecular Physiology 286 L694\u2013L700. (doi:10.1152\/ajplung.00204.2003)","DOI":"10.1152\/ajplung.00204.2003"},{"key":"2016051819135698000_23.4.265.71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0810790106"},{"key":"2016051819135698000_23.4.265.72","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.4A6438.2004"},{"key":"2016051819135698000_23.4.265.73","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3025"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/23\/4\/265.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/23\/4\/265.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:53:27Z","timestamp":1784555607000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/23\/4\/265-280\/34135"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4]]},"references-count":73,"journal-issue":{"issue":"4"},"URL":"https:\/\/doi.org\/10.1530\/erc-15-0505","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4]]}}}