Abstract
The insulin-like growth factor-I receptor (IGF-IR)3 is a transmembrane tyrosine kinaseregulating various biological processes such as proliferation, survival, transformation, differentiation,cell-cell and cell-substrate interactions. Different signaling pathways may underlie thesepleiotropic effects. The specific pathways engaged depend on the number of activated IGF-IRs,availability of intracellular signal transducers, the action of negative regulators, and is influencedby extracellular modulators. Experimental and clinical data implicate the IGF-IR in breastcancer etiology. There is strong evidence linking hyperactivation of the IGF-IR with theearly stages of breast cancer. In primary breast tumors, the IGF-IR is overexpressed andhyperphosphorylated, which correlates with radio-resistance and tumor recurrence. In vitro,the IGF-IR is often required for mitogenesis and transformation, and its overexpression oractivation counteract effects of various pro-apoptotic treatments. In hormone-responsive breastcancer cells, IGF-IR function is strongly linked with estrogen receptor (ER) action. TheIGF-IR and the ER are co-expressed in breast tumors. Moreover, estrogens stimulate the expressionof the IGF-IR and its major signaling substrate IRS-1, while antiestrogens downregulateIGF-IR signaling, mainly by decreasing IRS-1 expression and function. On the other hand,overexpression of IRS-1 promotes estrogen-independence for growth and transformation. InER-negative breast cancer cells, usually displaying a more aggressive phenotype, the levelsof the IGF-IR and IRS-1 are often low and IGF is not mitogenic, yet the IGF-IR is stillrequired for metastatic spread. Consequently, IGF-IR function in the late stages of breastcancer remains one of the most important questions to be addressed before rationalanti-IGF-IR therapies are developed.
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Surmacz, E. Function of the IGF-I Receptor in Breast Cancer. J Mammary Gland Biol Neoplasia 5, 95–105 (2000). https://doi.org/10.1023/A:1009523501499
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DOI: https://doi.org/10.1023/A:1009523501499