Morbidity from uterine leiomyomas affects an estimated four to fifteen million women in the United States. Despite the startling frequency at which these lesions occur, adequate therapeutic intervention strategies have not been developed. This report describes the characterization of a high incidence animal model for uterine leiomyoma development. In the Eker rat model, rats that inherit a mutation in one allele of a tumor susceptibility gene develop spontaneous reproductive tract leiomyomas. These tumors stained positively for smooth muscle markers, and increased in incidence with increasing animal age. Both benign and malignant lesions occurred, and seven cell lines were established from the Eker rat tumors. The cell lines were extensively characterized for expression of smooth muscle markers, growth factors, and steroid hormone receptors. Two of the cell lines were tumorigenic in nude mice. Estrogen stimulated proliferation of leiomyoma cells in vitro and in a nude mouse xenograft system in vivo, whereas the antiestrogen tamoxifen inhibited proliferation. The growth inhibition seen with tamoxifen did not correlate with estrogen receptor expression, but did correlate with expression of insulin-like growth factor-I (IGF-I). These data suggested that the growth-inhibitory effects of tamoxifen were associated with expression of IGF-I, and the existence of an IGF-I autocrine loop in the leiomyoma cells was therefore investigated. Cells concomitantly expressed IGF-I and its receptor. Exogenous IGF-I was mitogenic for leiomyoma cells in vitro, and neutralizing antibody to IGF-I inhibited the growth of these cells under serum-free conditions, establishing the existence of an IGF-I autocrine loop. IGF-I was able to partially rescue the growth inhibition seen with tamoxifen, supporting the hypothesis that tamoxifen modulates the growth of leiomyoma cells by interrupting an IGF-I autocrine loop. These data demonstrate the usefulness of the Eker rat model for rapid evaluation of efficacy and mechanism of action of therapeutic compounds in vitro. Combined with evaluation of therapeutic benefit in situ, it is therefore possible in a single model system to go from rapid in vitro screening to relevant determinations of efficacy in intact whole animals.