Our fundamental hypothesis for this study is that Insulin-like growth factor II (IGF-II) is an important regulator of the growth and malignant behavior of a significant subset of breast cancers. Insulin- like growth factor II is a potent mitogen for breast tumor epithelial cells. We have demonstrated that IGF-II can enhance the malignant behavior of breast tumors, and that it is expressed in the stromal component of the majority of breast cancers, possibly through loss of imprinting. In the subset of estrogen receptor negative breast cancers, IGD-II expression appears to be strongly associated with a poor prognosis. The goal of this proposal is to further define the mechanisms by which IGF-II regulates growth, and to design peptides based on the structure of the IGF-II/M6P receptor ligand binding domain which will inhibit IGF-II effects in breast cancer. We hypothesize that these peptides will have anti-tumor effects in breast cancer. The net cellular effects of IGF-II on breast cancer epithelium are determined by a balance of ligand expression, ligand degradation, and the ability of the ligand to bind to the IGF-I receptor and activate its tyrosine kinase. Recent data from our laboratory demonstrate that the IGF-II/M6P receptor serves inhibit the mitogenic effects of IGF-II, most likely by enhancing intracellular degradation of IGF-II before it has the opportunity to bind to the IGF-I receptor. Further, data from other laboratories indicate that inactivating mutations of the IGF-II/M6P receptor are common in hepatocellular carcinomas and in breast cancer, supporting the hypothesis that the IGF-II/M6P receptor serves as a tumor suppressor gene in breast cancer. The specific experimental aims for this study are: 1. To examine expression of IGF-II/M6P receptor in clinical breast cancer specimens and to correlate receptor expression with IGF-II ligand expression, prognostic variables and clinical outcome. 2. To examine IGF-II expression in early breast lesions, and evaluate the role of IGF-II in breast cancer progression. 3. To determine loss of imprinting of IGF-II by allele specific in situ hybridization in breast tumor biopsies. 4. To examine the utility of IGF-II/M6P receptor fragments as antitumor agents in breast cancer.
| Singer, C F; Rasmussen, A; Lippman, M E et al. (1997) Coexpression of stromelysin-3 and insulin-like growth factor II in tumors of ectodermal, mesodermal, and endodermal origin: indicator of a fetal cell phenotype. J Clin Endocrinol Metab 82:1917-22 |
| Ellis, M J; Leav, B A; Yang, Z et al. (1996) Affinity for the insulin-like growth factor-II (IGF-II) receptor inhibits autocrine IGF-II activity in MCF-7 breast cancer cells. Mol Endocrinol 10:286-97 |
| Singer, C; Rasmussen, A; Smith, H S et al. (1995) Malignant breast epithelium selects for insulin-like growth factor II expression in breast stroma: evidence for paracrine function. Cancer Res 55:2448-54 |
