PMID- 11752009
OWN - NLM
STAT- MEDLINE
DCOM- 20020123
LR  - 20250214
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 93
IP  - 24
DP  - 2001 Dec 19
TI  - Insulin-like growth factor-I receptor signaling and resistance to trastuzumab 
      (Herceptin).
PG  - 1852-7
AB  - 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.
FAU - Lu, Y
AU  - Lu Y
AD  - Department of Oncology, Jewish General Hospital, and McGill University, Montreal, 
      PQ, Canada.
FAU - Zi, X
AU  - Zi X
FAU - Zhao, Y
AU  - Zhao Y
FAU - Mascarenhas, D
AU  - Mascarenhas D
FAU - Pollak, M
AU  - Pollak M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Insulin-Like Growth Factor Binding Protein 3)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
CIN - J Natl Cancer Inst. 2001 Dec 19;93(24):1830-2. doi: 10.1093/jnci/93.24.1830. 
      PMID: 11752000
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology
MH  - Blotting, Western
MH  - Breast Neoplasms/drug therapy
MH  - Cell Division
MH  - Cell Survival
MH  - Dose-Response Relationship, Drug
MH  - *Drug Resistance, Neoplasm
MH  - Flow Cytometry
MH  - G1 Phase/drug effects
MH  - Humans
MH  - Insulin-Like Growth Factor Binding Protein 3/pharmacology
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Precipitin Tests
MH  - Receptor, ErbB-2/metabolism
MH  - Receptor, IGF Type 1/*metabolism
MH  - *Signal Transduction
MH  - Transfection
MH  - Trastuzumab
MH  - Tumor Cells, Cultured
EDAT- 2001/12/26 10:00
MHDA- 2002/01/24 10:01
CRDT- 2001/12/26 10:00
PHST- 2001/12/26 10:00 [pubmed]
PHST- 2002/01/24 10:01 [medline]
PHST- 2001/12/26 10:00 [entrez]
AID - 10.1093/jnci/93.24.1852 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2001 Dec 19;93(24):1852-7. doi: 10.1093/jnci/93.24.1852.