(CANCER RESEARCH 50. 48-53, January I, 1990] -like Expression and Function in Human Breast Cancer1

Kevin J. (alien, Douglas Yee, William S. Sly, James Perdue, Brian Hampton, Marc E. Lippman, and Neal Rosen Vincent T. Lombardi Cancer Research Center, Georgetown University, Washington, DC 20007 [K. J. C., D. Y., M. 'E. L.. N. R.J; St. Louis University School of Medicine, St. Louis, Missouri 63104 ¡W.S. S.J; and the Holland Research Labs, American Red Cross, Rockville, Maryland 20850 [J. P., B. H.J

ABSTRACT both IGF-I and IGF-II may have a growth-promoting role in human breast cancer. The insulin-like growth factors IGF-I and Idi -li are potent mitogens Distinct receptors for IGF-I and IGF-II have been described for several breast tumor cell lines in culture. Additionally, both IGF-I and cloned. The type I IGF receptor (IGF-I receptor) is a and IGF-II mRNAs are easily detected in the majority of breast tumor transmembrane heterotetramer structurally very similar to the specimens examined, while no breast cancer epithelial cell lines we have studied express authentic IGF-I mRNA, and few lines express IGF-II insulin receptor. It is composed of two «chains which comprise iiiRNA. Although receptors for insulin, IGF-I, and IGF-II have been the extracellular ligand binding domain, and two ,i chains which described, there is significant cross-reactivity between the various recep include the transmembrane region as well as an intracellular tors and ligands in the insulin/insulin-like growth factor family, and it is domain (9, 10). In contrast, the type II IGF not clear which receptor or receptors are responsible for the biological receptor (IGF-II receptor) exists as a single transmembrane effects of these growth factors in this system. chain with a small intracellular domain lacking apparent tyro- Using an RNase protection assay, we examined breast tumor speci sine kinase activity (11). The type II IGF receptor is also the mens and breast cancer epithelial cell lines for expression of mRNA receptor for marinóse 6-phosphate (12), a sugar moiety found encoding the type I and type II IGF receptors as well as the insulin in several glycoproteins which is important in the recognition receptor. Virtually all of the specimens examined expressed mRNA for and intracellular transport of soluble lysosomal enzyme precur all three receptors. We then examined estrogen-dependent MCF-7 cells for the mitogenic effects of IGF-I and II in the presence of antibodies to sors. Additionally, the type II receptor binds procathepsin D, a both the type I and type II receptors. aIR-3, a monoclonal antibody proteolytic enzyme produced in abundance by some breast which blocks the type I receptor, abolished the mitogenic effects of both cancer cells, which has also been reported to be a mitogen for IGF-I and IGF-II. It did not, however, block the mitogenic effects of breast tumor epithelial cells in culture (13). insulin. We conclude that type I and type II IGF receptors are ubiqui Considerable cross-reactivity takes place between the various tously expressed in breast cancer, and our experiments with MCF-7 cells ligands and receptors in the insulin/insulin-like growth factor suggest the mitogenic effects of both IGF-I and IGF-II are mediated via family (14). Insulin can bind to both the insulin receptor and the type I IGF receptor. the type I IGF receptor, while IGF-I and IGF-II can bind to the insulin receptor as well as the type I and type II IGF receptors. Evidence from a number of previous studies has INTRODUCTION suggested that at least some of the biological effects of IGF-II are mediated by the type I IGF receptor (15, 16). In human In recent years, an extensive literature has developed on the breast cancer, inhibition of growth of some tumor cell lines can role of peptide growth factors in the growth