Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer

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Abstract
The ligands, receptors and related signaling proteins of the insulin‐like growth factor family are involved in the regulation of breast‐cancer cell growth. We investigated the expression pattern of insulin‐like growth factor‐I receptor (IGF‐IR), insulin receptor (IR) and insulin receptor substrate‐1 (IRS‐1), a core downstream signaling protein, in 69 primary breast‐cancer specimens of different grades and in 21 control tissues by immunohistochemistry. In addition, cell proliferation (percentage of Ki67+ nuclei) and estrogen receptor (ER) expression were determined. IGF‐IR, IRS‐1 and IR were expressed mainly in epithelial cells. IRS‐1 and IGF‐IR were expressed at high levels in control tissues and in well and moderately differentiated carcinomas but at low levels in poorly differentiated breast cancers. IR expression did not show a significant correlation with the differentiation grade of the tissues investigated. Statistical analysis (ROC analysis for tumor grade) demonstrated that down‐regulation of IGF‐IR and IRS‐1 correlated better with tumor progression than reduction of ER expression or increase in cell proliferation, IGF‐IR showing the best correlation, followed by IRS‐1 and, less significant, ER and Ki67. Our findings clearly show that progression of breast cancer is accompanied by a reduction of IGF‐IR/IRS‐1 expression and that IGF‐IR/IRS‐1 expression inversely correlates with high proliferation rate in dedifferentiated breast cancers. The strong correlation of IGF‐IR and IRS‐1 down‐regulation with tumor progression suggests the use of IGF‐IR and IRS‐1 as a novel set of marker proteins for tumor grading. Int. J. Cancer 89:506–513, 2000.