title: Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in Müllerian duct mesenchyme-derived myometria.
abstract: Uterine leiomyomata are the most common tumors found in the female reproductive tract. Despite the high prevalence and associated morbidities of these benign tumors, little is known about the molecular basis of uterine leiomyoma development and progression. Loss of the Tuberous Sclerosis 2 (TSC2) tumor suppressor has been proposed as a mechanism important for the etiology of uterine leiomyomata based on the Eker rat model. However, conflicting evidence showing increased TSC2 expression has been reported in human uterine leiomyomata, suggesting that TSC2 might not be involved in the pathogenesis of this disorder. We have produced mice with conditional deletion of the Tsc2 gene in the myometria to determine whether loss of TSC2 leads to leiomyoma development in murine uteri. Myometrial hyperplasia and increased collagen deposition was observed in Tsc2(cKO) mice compared with control mice, but no leiomyomata were detected by post-natal week 24. Increased signaling activity of mammalian target of rapamycin complex 1, which is normally repressed by TSC2, was also detected in the myometria of Tsc2(cKO) mice. Treatment of the mutant mice with rapamycin significantly inhibited myometrial expansion, but treatment with the progesterone receptor modulator, mifepristone, did not. The ovaries of the Tsc2(cKO) mice appeared normal, but half the mice were infertile and most of the other half became infertile after a single litter, which was likely due to oviductal blockage. Our study shows that although TSC2 loss alone does not lead to leiomyoma development, it does lead to myometrial hyperplasia and fibrosis.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kaneko-Tarui
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Arno E
authors.initials: AE
authors.lastname: Commandeur
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Patterson
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: DeKuiper
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Styer
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA jose.teixeira@hc.msu.edu.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D005260:Female; D005298:Fertility / Q000235:genetics; D005355:Fibrosis / Q000235:genetics; D017353:Gene Deletion; D006965:Hyperplasia / Q000235:genetics; D007889:Leiomyoma / Q000235:genetics / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009095:Mullerian Ducts / Q000473:pathology*; D046912:Multiprotein Complexes / Q000378:metabolism; D009215:Myometrium / Q000473:pathology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: TSC2; infertility; mTOR; tumourigenesis; uterine fibroid