Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway.
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.
Crabtree
Judy S
JS
Endocrinology & Reproductive Disorders Division, Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania, USA.
Jelinsky
Scott A
SA
Harris
Heather A
HA
Choe
Sung E
SE
Cotreau
Monette M
MM
Kimberland
Michelle L
ML
Wilson
Ewa
E
Saraf
Kathryn A
KA
Liu
Wei
W
McCampbell
Adrienne S
AS
Dave
Bhuvanesh
B
Broaddus
Russell R
RR
Brown
Eugene L
EL
Kao
Wenling
W
Skotnicki
Jerauld S
JS
Abou-Gharbia
Magid
M
Winneker
Richard C
RC
Walker
Cheryl L
CL
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*
D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases