A pure antiestrogen, ICI 182,780, stimulates the growth of tamoxifen-resistant KPL-1 human breast cancer cells in vivo but not in vitro

The critical mechanisms responsible for antiestrogen resistance have not ye t been elucidated. We previously established a breast cancer cell line, KPL -1, derived from a patient with recurrent disease which appeared under tamo xifen administration. In a previous study, we suggested that this cell line is estrogen receptor (ER)-positive but tamoxifen-resistant. In the present study, the effects of a pure antiestrogen, ICI 182,780, on this cell line were investigated. Although tamoxifen inhibited neither cell growth nor est radiol-stimulated transcriptional activity in vitro, ICI 182,780, significa ntly inhibited both of them. Tamoxifen and ICI 182,780 were then administer ed to female nude mice bearing KPL-1 tumors. Tamoxifen had no effect on tum or growth, but ICI 182,780 unexpectedly stimulated it (p=0.022). Estradiol tended to inhibit tumor growth (p=0.198). Immunohistochemical analysis reve aled that ICI 182,780 significantly increased the Ki67-labeling index (p<0. 001) but estradiol decreased it (p=0.035). To explore the possible mechanis ms of these phenotypes, the mRNA levels of ER-alpha, ER-beta, transforming growth factor-beta 1, fibroblast growth factor (FGF)-1 and FGF-4 in KPL-1 c ells were compared with those in other ER-positive human breast cancer cell lines by reverse-transcription polymerase chain reaction. FGF-I was overex pressed only in KPL-1 cells. This cell line is the first breast cancer cell line to be growth-stimulated by ICI 182,780 in vivo. Paracrine interaction between tumor cells and stromal cells mediated by growth factors, such as FGF-1, might be a key factor to explain the unique hormone responsiveness o f KPL-1 cells.