Presence of an insulin-like growth factor I autocrine loop predicts uterine fibroid responsiveness to tamoxifen.

ABSTRACT

Uterine leiomyoma is an estrogen-responsive tumor, and the present studies examine the ability of the antiestrogen tamoxifen to modulate leiomyoma cell growth. Tamoxifen is an effective form of hormonal therapy for breast cancer, although the mechanism by which tamoxifen inhibits tumor growth is not well understood and may involve mechanisms other than the action of tamoxifen as an estrogen antagonist. Tamoxifen was found to inhibit the proliferation of three of five leiomyoma-derived cell lines (ELT cell lines) in vitro, including an estrogen receptor-negative cell line. The ability of tamoxifen to decrease leiomyoma growth was found to correlate with expression of insulin-like growth factor I (IGF-I) by the tumor cells, suggesting that the inhibitory effects of tamoxifen were associated with expression of this growth factor. The existence of an IGF-I autocrine loop in the cells was investigated, because transcripts for both IGF-I and its cognate receptor were expressed in the tamoxifen-responsive cell lines. An IGF-I RIA demonstrated secreted IGF-I protein in serum-free medium conditioned by the IGF-I-expressing cell line ELT 3, and this same medium supported the growth of IGF-requiring MCF-10A cells, indicating the presence of biologically active IGF-I in the conditioned medium. Exogenous IGF-I stimulated ELT 3 cell proliferation, confirming that this growth factor is mitogenic for leiomyoma cells. IGF-I neutralizing antibody inhibited ELT 3 growth, indicating that the levels of IGF-I produced by the leiomyoma cells were physiologically significant. These data demonstrate the existence of an IGF-I autocrine loop in tamoxifen-sensitive leiomyoma cells, supporting the hypothesis that the presence of an IGF-I autocrine loop predicts uterine fibroid responsiveness to tamoxifen.