Function of the IGF-I receptor in breast cancer

被引:204
作者
Surmacz, E [1 ]
机构
[1] Thomas Jefferson Univ, Kimmel Canc Inst, Philadelphia, PA 19107 USA
关键词
breast cancer; insulin-like growth factor I receptor; IRS-1; estrogen-independence; antiestrogen; metastasis;
D O I
10.1023/A:1009523501499
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The insulin-like growth factor-I receptor (IGF-IR)(3) is a transmembrane tyrosine kinase regulating various biological processes such as proliferation, survival, transformation, differentiation, cell-cell and cell-substrate interactions. Different signaling pathways may underlie these pleiotropic 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 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 and hyperphosphorylated, which correlates with radio-resistance and tumor recurrence. In vitro, the IGF-IR is often required for mitogenesis and transformation, and its overexpression or activation counteract effects of various pro-apoptotic treatments. In hormone-responsive breast cancer cells, IGF-IR function is strongly linked with estrogen receptor (ER) action. The IGF-IR and the ER are co-expressed in breast tumors. Moreover, estrogens stimulate the expression of the IGF-IR and its major signaling substrate IRS-1, while antiestrogens downregulate IGF-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. In ER-negative breast 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 IGF-IR is still required for metastatic spread. Consequently, IGF-IR function in the late stages of breast cancer remains one of the most important questions to be addressed before rational anti-IGF-IR therapies are developed.
引用
收藏
页码:95 / 105
页数:11
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