Alterations in plasma IGF-I caused by hormone manipulation; of relevance to the mechanism of action and acquired resistance to endocrine treatment in breast cancer?

Insulin-like growth factor-I (IGF-I) is a potent mitogen for breast cancer cells. Oestrogens, as well as androgens, modify plasma IGF-I levels. More recent investigations have revealed that antihormone treatment with tamoxifen suppresses plasma IGF-I. Treatment with luteinizing hormone-releasing hormone (LHRH) agonists also suppresses plasma IGF-I, but treatment with the aromatase inhibitor aminoglurethimide or the progestin megestrol acetate have both been found to elevate plasma IGF-I levels. Apart from influencing plasma levels of total IGF-I, endocrine therapy may act on IGF-I disposition by modifying the concentration of IGF-binding proteins. IGF-binding proteins play an important role in modulating the biological activity of IGF-I. Tamoxifen significantly elevates the concentration of IGF-binding protein-1 (IGFBP-1), whereas megestrol acetate has been found to inhibit a plasma protease modifying IGF-binding protein-3 (GFBP-3), leaving more of this binding protein in a 'high affinity' state for IGF-I. Thus not only alterations in IGF-I but also changes in IGF-binding proteins may interact with antiendocrine treatment in a complex manner. Such effects may add to treatment effectiveness but could also be detrimental to the antitumour effects of the drugs. Studies of alterations in the IGF-I system not only in relation to drug effects but also in relation to the emergence of resistance to endocrine therapy in breast cancer patients are warranted.