Comparison between novel steroid‐like and conventional nonsteroidal antioestrogens in inhibiting oestradiol‐ and IGF‐I‐induced proliferation of human breast cancer‐derived cells

This study has two specific aims: (a) to compare the antioestrogenic activity of two steroidal analogues of 17β‐oestradiol, the 7α‐alkylamide, ICI 164, 384 and the 7α‐alkylsulphinylamide, ICI 182, 780, with that of the triphenylethylene‐derived compound 4OH‐tamoxifen on a pool of human breast cancer cell lines (HBCCL) with a range of hormonal responsiveness and acquired antioestrogen resistance and (b) to investigate the ability of such antioestrogens to modulate the potent breast carcinoma growth‐stimulatory activity of the ‘IGF‐I system’. For the chemosensitivity investigations we used a long‐term colorimetric and the short‐term thymidine incorporation assay; we analysed IGF‐I in conditioned media by a radioimmunoassay, IGF‐I mRNA in the cells by RT‐PCR and molecular species of IGF‐I‐binding proteins, secreted in conditioned media, by Western ligand blot. IGF‐I receptors were assayed on cell monolayers by binding studies and by Scatchard analysis, we calculated KD, Bmax and sites/cell. Our results indicate that ICI 182, 780 and ICI 164, 384 are 1.5‐5.5 fold more potent than 40H‐tamoxifen in inhibiting the basal proliferation of oestrogen‐receptor positive (ER +) breast cancer cell lines. Moreover we demonstrate the capacity of ICI 182, 780 and ICI 164, 384 to reduce, in a time‐dependent fashion, oestrogen‐ and/or IGF‐I‐stimulated growth of ER + cell lines, possibly by negatively interfering with an IGF‐I‐like material secretion and IGF‐I‐receptor number. Our data provide the first evidence that, on ER+ human breast carcinoma cell lines, steroidal antioestrogens inhibit cell growth and modulate the IGF‐I mitogenic system. The mechanism of this latter effect has yet to be identified. 1995 British Pharmacological Societ