Regulation of insulin-like growth factors by antiestrogen.

Insulin-like growth factors are potent mitogens for breast cancer cell proliferation. This effect is modulated by the circulatory and extracellular IGFBPs as well as by the affinity of ligand binding receptors on the target cells. Antiestrogens have been shown to reduce both circulatory and microenvironmental IGF levels and thus suppress the IGF-I-induced growth of both ER-positive and ER-negative breast cancer cells. However, the effects of antiestrogens in down regulation of type I IGF receptor and in altering the autophosphorylation tyrosine kinase activity of EGF receptors are mainly observed in ER-positive cells. Furthermore, alteration of IGFBP by antiestrogens such as a marked increase of IGFBP-I production have been shown to inhibit the proliferative effect of IGF-I on ER-positive, but stimulate this effect, on ER-negative cells. Such differential effects from IGF receptor and IGFBP may explain the clinical outcome that tumor regression from antiestrogens is mainly observed in ER-positive type. This assumption based on IGF regulation alone is certainly an oversimplistic view amid the complexity of autocrine, paracrine, and endocrine functions.