title: Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway.
abstract: Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyomata. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyomata. An unbiased pathway analysis using a method of gene-set enrichment based on the sigPathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly up-regulated pathways in both human and rat tumors. To validate this pathway as a therapeutic target for uterine leiomyomata, preclinical studies were conducted in Eker rats. These rats develop uterine leiomyomata as a consequence of loss of Tsc2 function and up-regulation of mTOR signaling. Inhibition of mTOR in female Eker rats with the rapamycin analogue WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity, and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly show the dependence of uterine leiomyomata with activated mTOR on this signaling pathway for growth.
authors.affiliation: Endocrinology & Reproductive Disorders Division, Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania, USA.
authors.forename: Judy S
authors.initials: JS
authors.lastname: Crabtree
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jelinsky
authors.forename: Heather A
authors.initials: HA
authors.lastname: Harris
authors.forename: Sung E
authors.initials: SE
authors.lastname: Choe
authors.forename: Monette M
authors.initials: MM
authors.lastname: Cotreau
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Kimberland
authors.forename: Ewa
authors.initials: E
authors.lastname: Wilson
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Saraf
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: McCampbell
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Dave
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Brown
authors.forename: Wenling
authors.initials: W
authors.lastname: Kao
authors.forename: Jerauld S
authors.initials: JS
authors.lastname: Skotnicki
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: Richard C
authors.initials: RC
authors.lastname: Winneker
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Walker
mesh_terms: D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism*; D009215:Myometrium / Q000378:metabolism / Q000502:physiology; D040081:Protein Array Analysis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases