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. [Cancer Res 2009;69(15):6171-8]

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

“…In addition, they found that E 2 treatment increases PTEN in leiomyoma, but not in myometrial cells. Finally, Crabtree and colleagues (94) found upregulated mTOR pathways in leiomyoma, both in human and in the Eker rat animal model. These findings suggest that aberrant PI3K/Akt/mTOR signaling plays a role in leiomyoma pathobiology.…”

Lymphangioleiomyomatosis andTSC2-/-Cells

“…107 Like the proliferative smooth muscle cells of LAM lesions, these lines are Tsc2-null and have constitutively active mTORC1 signaling. 108 More importantly, these lines express estrogen and progesterone receptors, and retain their hormone responsiveness. 109,110 Isogenic ELT3 cell lines, T3 and V3, reexpressing Tsc2 or vector control, respectively, have also been generated.…”

Increased expression of tuberin in human uterine leiomyoma

“…Transcriptional profiling of leiomyomas from humans and rats has revealed an up-regulation of mRNA levels of some components in the mTOR pathway compared with normal myometrium. In addition, inhibition of the mTOR pathway by rapamycin analogue WAY-129327 reduces leiomyoma incidence in female Eker rats (9).…”