Function of the IGF-I receptor in breast cancer.
The insulin-like growth factor-I receptor (IGF-IR) 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.
Surmacz
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Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. surmacz1@jeflin.tju.edu
D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D015398:Signal Transduction
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D017526:Receptor, IGF Type 1