Effects of antioestrogens on the proliferation of MCF-7 human breast cancer cells

Abstract

Non-steroidal antioestrogens, such as tamoxifen, inhibit the growth of human breast cancer cells. The experiments described here compare and contrast the efficacy of tamoxifen and the 'pure' antioestrogen, ICI 164384, on the inhibition of proliferation of MCF-7 cells. Previous studies have shown that ICI 164384 has a greater maximal inhibitory effect than conventional antioestrogens on the growth of MCF-7 cells. Both types of compound block progression of cells through the cell cycle in the early G1 phase. These studies have been extended to measure the population distribution of antioestrogen-treated cells by the use of two-parameter flow cytometry. ICI 164384 proved to be more effective than tamoxifen in decreasing the proportion of actively growing cells in an asynchronous population. In cells grown in the complete absence of exogenous oestrogens, growth was stimulated by oestradiol, insulin, insulin-like growth factor-I (IGF-I) or transforming growth factor-alpha (TGF-alpha). The potent metabolite of tamoxifen, trans 4'-hydroxytamoxifen (4'-OHT), alone also stimulated growth, whereas ICI 164384 did not. Oestradiol and insulin added together demonstrated a clear synergistic enhancement of cell growth. Correspondingly, the stimulatory effect of 4'-OHT on growth was magnified in the presence of insulin, and a combination of ICI 164384 with insulin revealed a much weaker stimulatory action of the 'pure' antagonist. For both compounds the interaction with insulin was complex and characterized by a bell-shaped dose-response curve. However, for 4'-OHT at all concentrations in the range 1 pM-1 microM in the presence of insulin, cell numbers were greater than in cultures exposed to insulin alone. This was not the case for ICI 164384 which suggested that differences in efficacy may be due to interactions between oestrogen and growth factor-mediated mechanisms. Furthermore, ICI 164384 was more effective in inhibiting the action of IGF-I and TGF-alpha alone or in combination, although both antioestrogens produced a partial blockade of growth factor responses in the complete absence of oestradiol. It is concluded that the difference in efficacy between partial agonist and 'pure' antagonist antioestrogens to inhibit growth in vitro is consistent with the difference in the pharmacological profile of these compounds. The absence of stimulatory activity of ICI 164384 is of particular significance in reducing to a minimum the synergistic interaction between oestrogens and insulin.(ABSTRACT TRUNCATED AT 400 WORDS)

Co-stimulation of gastrointestinal tumour cell growth by gastrin, transforming growth factor α and insulin like growth factor-I

“…The mitogenic responses induced by IGF-I and TGFa were additive suggesting that the two growth factors act independently at their different receptors to stimulate cell growth. Similar results have also been observed for breast cancer cells (Wakeling et al, 1989).…”

“…Earlier studies have shown that drugs which alter gastrin secretion Watson et al, 1989d) or block gastrin binding Watson et al, 1989aJ) can inhibit growth of human gastrointestinal tumours growing in nude mice. Whether these drugs or new drugs can act like the anti-oestrogen drug, tamoxifen, (Lippman et al, 1986;Wakeling et al, 1989) and also prevent growth factor secretion remains to be examined. In this context it is interesting that both TGFa and IGF-I have been suggested as autocrine growth factors for gastrointestinal cancers.…”

Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro

“…These clinical findings are supported by the results of laboratory studies with established human breast cancer cell lines, showing stimulation of cell growth by tamoxifen both in vitro (Darbre et al 1984;Reddel & Sutherland, 1984;Katzenellenbogen et al, 1987;Wakeling et al, 1989) and in vivo (Gottardis & Jordan, 1988). However, the relevance of these experimental studies to human breast cancer may be diminished by alterations in endocrine responsiveness that immortalised breast cancer cell lines may undergo during long-term cultivation (Simon et al, 1984a).…”

“…The lack of activity of ICI 182780 in ER-negative Hs578T cells seen in the present study suggests that the antiproliferative effects of this agent in MCF-7 cells were ER dependent and were not due to non-specific cytotoxicity. (Roos et al, 1982;Darbre et al, 1984;Reddel & Sutherland, 1984;Katzenellenbogen et al, 1987;Thompson et al, 1989;Wakeling et al, 1989) but not by the pure antioestrogens ICI 164384 or ICI 182780 (Thompson et al, 1989;Wakeling et al, 1991).…”

Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer

“…The specific anti-oestrogens have also been shown to produce a rapid reduction of intracellular ER levels, possibly as a result of inhibition of ER dimerisation and reduction of the ER halflife (Fawell et al, 1990;Dauvois et al, 1992). This latter effect is in contrast to that of tamoxifen, which has been shown to increase ER expression by breast cancer cells in vitro (Wakeling et al, 1989).…”