PRECLINICAL STUDIES ON HUMAN FIBROIDS IN IMMUNODEFICIENT MICE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Uterine fibroids (leiomyomata) are benign tumors of the uterine muscle or myometrium that affect 25-40% of women of reproductive age. Despite the high prevalence of fibroids in reproductive-age women, there are few animal models for fibroid disease. To fill this gap we created a human xenograft model for preclinical studies of human fibroids. Fibroids are collected from women undergoing hysterectomy and transplanted into immunodeficient SCID mice for study. Our goal was to test the effects of novel anti-fibroid therapies including androgens and androgen antagonists on growth of fibroid and myometrial grafts in these mice. The phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway may participate in steroid regulation of cell proliferation in fibroid cells. The mammalian target for rapamycin is a downstream mediator of PI3K/Akt. We tested the effect of rapamycin, and BEZ35 (a rapamycin analog) on fibroid graft growth. The mice bearing the grafts were treated with implants releasing either estradiol (E2), progesterone (P), E2 + P, E2 + P + Rapamycin, or and E2 + P + BEZ235. Rapamycin significantly reduce fibroid growth in our mouse model. BEZ235 did not reduce graft size, but did reduce fibroid cell proliferation. We have now also conducted studies with several androgen receptor modulators. We report that Androstenedione, eF-MENT a synthetic androgen, and DHT can reduce growth of human fibroid grafts in this system.