Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma

Uterine leiomyomas appear during the reproductive years and regress after m enopause, indicating the ovarian steroid-dependent growth potential. In ord er to characterize the molecular mechanism of sex steroidal regulation of l eiomyoma growth, we examined whether sex steroids could influence the proli feration of leiomyoma cells. As epidermal growth factor (EGF) has been show n to mediate estrogen action and play a crucial role in regulating leiomyom a growth, we also investigated the effects of sex steroids on EGF and EGF r eceptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cel ls, the addition of either estradiol (E-2; 10 ng/ml) or progesterone (P-4; 100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (P CNA) expression in the cells, whereas in cultures of normal myometrial cell s, the addition of E-2 augmented PCNA expression in the cells, but P-4 did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreac tive EGF and that P-4 treatment resulted in an increase in EGF expression i n the cells, whereas E-2 treatment resulted in a lower EGF expression in th e cells. By contrast, E-2 treatment augmented EGF-R expression in cultured leiomyoma cells, but P-4 did not. These results indicate that P-4 upregulat es the expression of PCNA and EGF in leiomyoma cells, whereas E-2 upregulat es the expression of PCNA and EGF-R in those cells. It is, therefore, conce ivable that P-4 and E-2 act in combination to stimulate the proliferative p otential of leiomyoma cells through the induction of EGF and EGF-R expressi on. We also found that bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometriu m and that Bcl-2 protein expression in leiomyoma cells was upregulated by P -4, but downregulated by E-2 It seems, therefore, likely that P-4 may also participate in leiomyoma growth through the induction of Bcl-2 protein in l eiomyoma cells. The abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of a leiomyoma r elative to that of normal myometrium in the uterus.