Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin).
BACKGROUND
Trastuzumab (Herceptin), an anti-HER2/neu receptor monoclonal antibody that inhibits growth of ErbB2-overexpressing breast cancer, is used to treat such cancers. Development of resistance to trastuzumab, however, is common. We investigated whether insulin-like growth factor-I (IGF-I), which activates cell survival signals, interferes with the growth-inhibitory action of trastuzumab.


METHODS
MCF-7/HER2-18 and SKBR3 human breast cancer models were used to assess cell proliferation, colony formation in soft agar, and cell cycle parameters. Throughout, we used trastuzumab at a dose of 10 microg/mL and IGF-I at a dose of 40 ng/mL. All statistical tests were two-sided.


RESULTS
Trastuzumab inhibited the growth of MCF-7/HER2-18 cells, which overexpress HER2/neu receptors and express IGF-I receptors (IGF-IRs), only when IGF-IR signaling was minimized. For example, in 1% fetal bovine serum (FBS), trastuzumab reduced cell proliferation by 42% (P =.002); however, in 10% FBS or IGF-I, trastuzumab had no effect on proliferation. In SKBR3 cells, which overexpress HER2/neu receptor but express few IGF-IRs, trastuzumab reduced proliferation by 42% (P =.008) regardless of IGF-I concentration. When SKBR3 cells were genetically altered to overexpress IGF-IRs and cultured with IGF-I, trastuzumab had no effect on proliferation. However, the addition of IGF-binding protein-3, which decreased IGF-IR signaling, restored trastuzumab-induced growth inhibition.


CONCLUSIONS
In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab. Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab.
Lu
Y
Y
Department of Oncology, Jewish General Hospital, and McGill University, Montreal, PQ, Canada.
Zi
X
X
Zhao
Y
Y
Mascarenhas
D
D
Pollak
M
M
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D002455:Cell Division; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D011233:Precipitin Tests; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab