Growth inhibition of human breast cancer cells in vitro with an antibody against the type I somatomedin receptor.
Insulin and insulin-like growth factors (IGFs) stimulate the growth of human breast cancer cells in vitro. The type I somatomedin receptor (SR), expressed in these cells, may mediate the mitogenic effects of these peptides. We have examined the effect of type I SR blockade on human breast cancer growth with a monoclonal antibody (alpha-IR3) that blocks the receptor binding domain. alpha-IR3 inhibited binding of 125I-IGF-I in all breast cancer cell lines tested. Binding affinity of alpha-IR3 was 2 to 5 times higher than that of IGF-I in MDA-231 (Kd 2.1 nM) and MCF-7 cells (Kd 0.6 nM), respectively. In the presence of 10% calf serum, the antibody inhibited anchorage-independent growth of six of seven breast cancer cell lines. This inhibition was reversible with excess IGF-I. In serum-free medium, alpha-IR3 blocked IGF-I-stimulated DNA synthesis in four of four breast cancer cell lines (MCF-7, ZR75-1, MDA-231, and HS578T). However, the antibody did not inhibit basal growth of any of the breast cancer cell lines in serum-free conditions. In three estrogen receptor-positive, estrogen-responsive breast cancer cell lines (MCF-7, ZR75-1, and T47D), type I SR blockade with alpha-IR3 failed to block estrogen-stimulated DNA synthesis or cell proliferation, indicating that secreted IGF activity is not the sole mediator of the growth effects of estrogen. In conclusion, antibody-mediated type I SR blockade does not inhibit basal growth of breast cancer cells under serum-free conditions, arguing against a critical autocrine role of endogenously secreted IGF activity in vitro. However, type I SR blockade inhibits breast cancer cell growth in the presence of serum, suggesting that serum IGFs might be critical endocrine or paracrine regulators of human breast cancer.
Arteaga
C L
CL
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7884.
Osborne
C K
CK
D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D007700:Kinetics; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins / Q000378:metabolism; D013002:Somatomedins / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000911:Antibodies, Monoclonal; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D013002:Somatomedins; D004958:Estradiol; D007334:Insulin-Like Growth Factor I