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 cirulatory and extrace llular IGFBPs as well as by the affinity of ligand binding receptors o n the target cells. Antiestrogens have been shown to reduce both circu latory and microenvironmental IGF levels and thus suppress the IGF-I-i nduced growth of both ER-positive and ER-negative breast cancer cells. However, the effects of antiestrogens in down regulation of type I IG F receptor and in altering the autophosphorylation tyrosine kinase act ivity of EGF receptors are mainly observed in ER-positive cells. Furth ermore, alteration of IGFBP by antiestrogens such as a marked increase of IGFBP-I production have been shown to inhibit the proliferative ef fect of IGF-I on ER-positive, but stimulate this effect, on ER-negativ e cells. Such differential effects from IGF receptor and IGFBP may exp lain the clinical outcome that tumor regression from antiestrogens is mainly observed in ER-positive type. This assumption based on IGF regu lation alone is certainly an oversimplistic view amid the complexity o f autocrine, paracrine, and endocrine functions.