Effect of simultaneous inhibition of epidermal growth factor receptor and cyclooxygenase-2 in HER-2/neu-positive breast cancer.
OBJECTIVE
HER-2/erbB2/neu is overexpressed in 25% to 30% of all invasive breast cancers and is associated with an aggressive course and reduced survival. HER-2/erbB2/neu breast tumors are frequently associated with up-regulation of cyclooxygenase (COX)-2 and activation of the epidermal growth factor receptor (EGFR) pathway, which promote enhanced cell growth and resistance to apoptosis. This study investigated whether simultaneously blocking both EGFR and COX-2 pathways with ZD1839 and celecoxib, respectively, would be more effective in inhibiting cell growth and inducing apoptosis than either agent alone.


METHODS
The effects of ZD1839, celecoxib, and their combination on cell survival, cell cycle progression, and apoptosis were determined in NMF11.2 mouse mammary tumor cells. We also investigated the potential downstream EGFR-activated pathways that are altered by simultaneous inhibition of COX-2 and EGFR.


RESULTS
Celecoxib alone and ZD1839 alone produced a concentration- and time-dependent inhibition of cell survival. Both agents combined produced supra-additive inhibitory effects on cell survival and apoptosis compared with either agent alone. This effect was associated with increased cleaved poly(ADP-ribose)polymerase and reduced protein expression of bcl-2. Phosphorylation of extracellular signal-regulated kinase 1/2 was partially blocked by ZD1839 and celecoxib alone and was completely blocked by the combination of both agents. The enhanced proapoptotic effects of the combined agents were also associated with decreased phosphorylation of Akt and increased phosphorylation of p38.


CONCLUSIONS
These findings show that both COX-2 and EGFR are important targets for inhibiting survival and inducing apoptosis in breast cancer. The data suggest a potential cross-talk between COX-2 and EGFR signaling in breast cancer cells overexpressing HER-2/erbB2/neu.
Lanza-Jacoby
Susan
S
Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Susan.Lanza-Jacoby@jefferson.edu
Burd
Randy
R
Rosato
Francis E
FE
McGuire
Kandace
K
Little
James
J
Nougbilly
Noel
N
Miller
Sheldon
S
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*
D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases