Interactions Between the Oestrogen and Insulin-like Growth Factor Signalling Pathways in the Control of Breast Epithelial Cell Proliferation

There is increasing evidence for interactions between steroid and growth factor signalling pathways. Oestrogens modulate the responsiveness of breast epithelial cells to insulin-like growth factors (IGFs), and this may be the mechanism by which oestrogens modulate cell proliferation. Oestrogens appear to act at several points in the IGF signal transduction pathway. Despite earlier studies suggesting that breast epithelial cells do not synthesize IGF-I, we have shown by PCR that IGF-I is expressed and that its expression is regulated by oestrogen. IGF-II is expressed at markedly higher levels than IGF-I and is also regulated by oestrogen, consistent with it being an oestrogen-regulated autocrine growth factor. Oestrogens regulate the expression of IGF binding proteins and the type I IGF receptor. The biological significance of oestrogen regulation of IGF binding protein expression is not clear. Experiments in which the type I IGF receptor has been constitutively overexpressed have suggested that oestrogen regulation of the receptor is not involved in mediating the effects of oestrogen on cell proliferation. Recent studies have started to assess the effects of oestrogen on the expression of components of the IGF signal transduction pathway, and have shown that the expression of insulin receptor substrate-1, the principal substrate for the tyrosine kinase of the type I IGF receptor, is regulated by oestradiol.