Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells.

Tamoxifen inhibited the oestrogen-stimulated proliferation of MCF-7 cells but had little effect on the oestrogen-stimulated proliferation of two tamoxifen-resistant variants (RL-3 and AL-1). The lack of oestrogen antagonist activity in the resistant cells was largely a result of an increased oestrogen agonist activity of tamoxifen on cell proliferation. Proliferation of the tamoxifen-resistant cells was also stimulated by 4-hydroxytamoxifen but not by ICI 164,384, a structurally distinct pure anti-oestrogen. Tamoxifen does not have increased oestrogen agonist activity for the induction of a series of oestrogen-regulated RNAs, and this suggests that the increased agonist activity may be restricted to key components involved in the proliferative response. Tamoxifen-stimulated cell proliferation was dependent on insulin-like growth factor I (IGF-1) in the resistant cells, suggesting that tamoxifen stimulates cell proliferation by sensitising cells to the proliferative effects of IGF-1. This may involve induction of the type-I IGF receptor.