Regulation of apoptosis in uterine leiomyomata

Tumors developing from hormone-dependent tissues, such as the breast and prostate, have been successfully treated in the clinic by methods of hormone ablation, and the resulting tumor regression has been shown to occur at least in part by the process of apoptosis. The growth of leiomyomas arising from uterine smooth muscle cells is similarly modulated by circulating steroid hormones and has been associated with periods of increased estrogen secretion. The inhibition of ovarian hormone production by endocrine therapy often results in the regression of these tumors, but the role of apoptosis in this process has not been elucidated. Using cell lines derived from the Eker rat model of uterine leiomyoma, we have investigated the mechanism of growth inhibition by estrogen deprivation. Estrogen-depleted medium and the antiestrogen tamoxifen significantly reduced cell numbers in culture and arrested cell proliferation, but did not induce apoptosis. However, the presence of an intact apoptotic pathway was demonstrated in these cells by serum starvation. In vivo data were in agreement with in vitro results, which showed that tamoxifen treatment does not change the apoptotic rate of leiomyoma tissues. Therefore, growth modulation of leiomyomas by hormone deprivation occurs via mechanisms independent of apoptosis, indicating a fundamental difference in the response of leiomyomas to hormone deprivation from that of tumors of the breast and prostate. These data suggest that creation of a hypoestrogenic milieu within leiomyomas reduces tumor volume without inducing a concomitant increase in the rate of apoptosis, which may be responsible for the limited effectiveness of currently available medicinal therapies.