Function of the IGF-I receptor in breast cancer

The insulin-like growth factor-I receptor (IGF-IR)(3) is a transmembrane ty rosine kinase regulating various biological processes such as proliferation , survival, transformation, differentiation, cell-cell and cell-substrate i nteractions. Different signaling pathways may underlie these pleiotropic ef fects. The specific pathways engaged depend on the number of activated IGF- IRs, availability of intracellular signal transducers, the action of negati ve regulators, and is influenced by extracellular modulators. Experimental and clinical data implicate the IGF-IR in breast cancer etiology. There is strong evidence linking hyperactivation of the IGF-IR with the early stages of breast cancer. In primary breast tumors, the IGF-IR is overexpressed an d hyperphosphorylated, which correlates with radio-resistance and tumor rec urrence. In vitro, the IGF-IR is often required for mitogenesis and transfo rmation, and its overexpression or activation counteract effects of various pro-apoptotic treatments. In hormone-responsive breast cancer cells, IGF-I R function is strongly linked with estrogen receptor (ER) action. The IGF-I R and the ER are co-expressed in breast tumors. Moreover, estrogens stimula te the expression of the IGF-IR and its major signaling substrate IRS-1, wh ile antiestrogens downregulate IGF-IR signaling, mainly by decreasing IRS-1 expression and function. On the other hand, overexpression of IRS-1 promot es estrogen-independence for growth and transformation. In ER-negative brea st cancer cells, usually displaying a more aggressive phenotype, the levels of the IGF-IR and IRS-1 are often low and IGF is not mitogenic, yet the IG F-IR is still required for metastatic spread. Consequently, IGF-IR function in the late stages of breast cancer remains one of the most important ques tions to be addressed before rational anti-IGF-IR therapies are developed.