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

Int J Cancer. 2000 Nov 20;89(6):506-13. doi: 10.1002/1097-0215(20001120)89:6<506::aid-ijc7>;2-f.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Lobular / genetics
  • Carcinoma, Lobular / metabolism
  • Carcinoma, Lobular / pathology
  • Cell Division / physiology
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin Receptor Substrate Proteins
  • Middle Aged
  • Phosphoproteins / biosynthesis*
  • Phosphoproteins / genetics
  • Receptor, IGF Type 1 / biosynthesis*
  • Receptor, IGF Type 1 / genetics
  • Receptor, Insulin / biosynthesis
  • Receptor, Insulin / genetics
  • Receptors, Estrogen / biosynthesis


  • Biomarkers, Tumor
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Receptors, Estrogen
  • Receptor, IGF Type 1
  • Receptor, Insulin