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Title: Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation.

Authors: Turner, B C; Haffty, B G; Narayanan, L; Yuan, J; Havre, P A; Gumbs, A A; Kaplan, L; Burgaud, J L; Carter, D; Baserga, R; Glazer, P M

Published In Cancer Res, (1997 Aug 1)

Abstract: The insulin-like growth factor-I receptor (IGF-IR) plays a critical role in cell growth regulation and transformation. The radiosensitivity of NIH 3T3 fibroblasts overexpressing either wild-type or mutant IGF-IR was examined. High levels of wild-type IGF-IR conferred radioresistance, and mutational analysis revealed that this effect correlated with the transforming capacity but not the mitogenic activity of the receptor. The radioresistant phenotype was reversed when the cells were incubated with antisense oligonucleotides targeted to IGF-IR mRNA, demonstrating that IGF-IR directly influences radioresistance. The clinical significance of these findings was examined in an immunohistochemical analysis of primary breast tumors, revealing that high levels of IGF-IR in tumor samples were highly correlated with ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy (P = 0.001). Subgroup analysis revealed that, for early breast tumor relapses (within 4 years of initial breast tumor diagnosis), elevated levels of IGF-IR were strongly associated with IBTR (P = 0.004) but IGF-IR expression was not prognostic for IBTR from breast cancer patients with late relapses (P was not significant). These studies provide evidence for the influence of IGF-IR on cellular radioresistance and response to therapy and raise the possibility that the radiocurability of selected tumors may be improved by pharmaceutical strategies directed toward the IGF-IR.

PubMed ID: 9242428 Exiting the NIEHS site

MeSH Terms: 3T3 Cells; Animals; Breast Neoplasms/metabolism*; Breast Neoplasms/radiotherapy; Breast Neoplasms/therapy; Humans; Immunohistochemistry; Mastectomy, Segmental; Mice; Neoplasm Recurrence, Local/metabolism; Oligonucleotides, Antisense/pharmacology; Radiation Tolerance/drug effects; Radiotherapy, Adjuvant; Receptor, IGF Type 1/genetics; Receptor, IGF Type 1/metabolism*; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Transfection

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