Levels of
prostaglandin E(2) (
PGE(2)) in human and rodent breast
cancers are higher than surrounding normal tissues.
PGE(2) exhibits
biological activity through binding to membrane receptors, EP(1-4). The present study was designed to investigate the effects of
ONO-8711, a newly synthesized selective
PGE receptor EP(1) antagonist, on 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (
PhIP)-induced
breast cancer development. Starting at 7 weeks of age, female Sprague-Dawley (SD) rats were given
PhIP (85 mg/kg
body weight) by gavage four times weekly for two weeks. Dietary administration of
ONO-8711 at 400 or 800 p.p.m. delayed occurrence of
breast tumors for 2 or 4 weeks, respectively. At 20 weeks after the last dosing of
PhIP, all animals were killed and complete autopsy was made. All
breast tumors were diagnosed as invasive ductal
adenocarcinomas histopathologically. Administration of
ONO-8711 at 800 p.p.m. significantly decreased
PhIP-induced
breast cancer incidence, multiplicity and volume compared with those of rats fed the control diet (56% versus 79%, P < 0.05, 1.2 versus 2.5, P < 0.05, 0.7 versus 1.4 cm(3), P < 0.01, respectively). Apoptosis was significantly increased in
breast cancer cells by feeding of
ONO-8711 at 800 p.p.m. of 158% (P < 0.05). EP(1) receptor was detected by reverse transcription-polymerase chain reaction (RT-PCR) in breast
cancers, not in normal tissues. These results suggest that EP(1) receptor is associated with
breast cancer development and selective
PGE receptor EP(1) antagonists may possess chemopreventive effects through the induction of apoptosis without any side effects.