title: Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model.
abstract: 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 (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 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 Tsc2-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 Tsc2-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 Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-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 Tsc2-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.
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Hen
authors.initials: H
authors.lastname: Prizant
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Taya
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Lerman
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Light
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Aritro
authors.initials: A
authors.lastname: Sen
authors.affiliation: Department of Imaging SciencesUniversity of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Department of Imaging SciencesUniversity of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Foster
authors.affiliation: Division of Endocrinology and MetabolismDepartment of Medicine, University of Rochester Medical Center, Rochester, New York, USA stephen_hammes@urmc.rochester.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hammes
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D018192:Lymphangioleiomyomatosis / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology; D014599:Uterus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D004967:Estrogens; D005136:Eye Proteins; C503042:GPNMB protein, human; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D004958:Estradiol; D019272:Leukocyte Elastase; D020782:Matrix Metalloproteinases
keywords: GPNMB; estrogen; lymphangioleiomyomatosis; mTOR; metalloproteinase; uterus