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Molecular mechanisms of steroid hormone action
1 Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, UK The ability of oestrogens and androgens to stimulate the growth of a number of endocrine cancers is well established and several endocrine therapies are widely used to reduce the availability of the hormones or to block their action. These include non-steroidal hormone antagonists such as tamoxifen and flutamide, steroidal compounds which include ICI 182780 and cyproterone acetate, and both steroidal and non-steroidal aromatase inhibitors. Although we have learned a great deal about the molecular mechanism of steroid hormone action, it is still unclear as to how hormones stimulate the proliferation of tumour cells and how hormone antagonists function. In part this is a result of the ability of oestradiol and testosterone to regulate the expression of many proteins implicated in the control of cell proliferation making it difficult to identify the crucial targets. Some of these targets are growth factors and/or their receptors which suggests that the mitogenic effects of steroids may be mediated by indirect autocrine or paracrine mechanisms (Clarke et al. 1991, Roberts and Sporn 1992). Alternatively since steroids regulate the expression of certain cyclins or kinase inhibitors (Musgrove and Sutherland 1994, Altucci et al. 1996) they may control cell cycle progression directly. Recent work suggests that as well as the cyclin D1 gene, cyclin D1 itself may be a crucial target (Zwijsen et al. 1997) but additional proteins could also be important in different subsets of tumours. The identification of target genes for steroid hormones is further complicated by the observation that receptor signalling is cross-coupled with that of other signalling pathways. It used to be thought that signalling by receptors was relatively straightforward compared with most other signalling pathways, since the receptor itself is a transcription factor. It is now clear however, that growth factors, neurotransmitters and other hormones are able to modulate the activity of steroid hormone receptors (Power et al. 1991, Aronica and Katzenellenbogen 1993, Ignar-Trowbridge et al. 1993 ). This means that alterations in the activity of receptors and the expression of individual target genes involved in cell proliferation is determined not only by hormonal signals but also by changes in other signalling pathways, which undoubtedly take place during breast and prostate cancer progression. Receptors are also capable of regulating the activity of a number of other transcription factors, either directly or indirectly, and thereby modulate the ability of other signalling pathways to control gene transcription (Shemshedini et al. 1991, Philips et al. 1993, Stein and Yang 1995, Webb et al. 1995). Although the precise role of steroid hormones in cell proliferation is still ill-defined, tremendous progress has been made in elucidating the role of hormones in receptor activation and the mechanism by which hormone antagonists block this activity. In particular two recent advances have been made which provide new insights into steroid hormone action and the function of nuclear receptors in general. Firstly, models for the three-dimensional structure of the ligand binding domain of several receptors have been determined (Bourguet et al. 1995, Renaud et al. 1995, Wagner et al. 1995) and secondly, novel proteins have been identified (Halachmi et al. 1994, Cavaillés et al. 1994) which interact with receptors in a ligand dependent manner and may play a role in gene transcription. These developments are helping to provide a better understanding of the mechanism of action of both hormones agonists and antagonists and the links between nuclear receptors and other signalling pathways. In this review we will outline these advances, with reference to the oestrogen receptor, and discuss their relevance to antioestrogen therapy and tamoxifen resistance.
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