Insulin-like growth factors in human breast cancer

IGF1 and IGF2 are circulating peptide hormones and locally-acting growth fa ctors with both paracrine and autocrine functions. IGF1 and IGF2 signal thr ough a common tyrosine kinase receptor, the insulin-like growth factor 1 re ceptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and br east development. The activities of IGF1 and 2 are tightly-regulated by a n etwork of binding proteins and targeted degradation mechanisms. This comple x regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infi ltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 rec eptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degr adation; c) IGF1R is overexpressed by malignant breast epithelial cells, an d in some cases IGF1R is amplified; and d) complex changes in IGF binding p rotein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenet ic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxi c stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of the se findings, we propose that IGF analysis of breast cancer samples should s hift from prognostic studies to an evaluation of IGF ligands, receptors, an d binding proteins as resistance/sensitivity markers for radiation, chemoth erapy, and endocrine therapy.