title: CDDO-methyl ester delays breast cancer development in BRCA1-mutated mice.
abstract: The breast cancer-associated gene 1 (BRCA1) is the most frequently mutated tumor suppressor gene in familial breast cancers. Mutations in BRCA1 also predispose to other types of cancers, pointing to a fundamental role of this pathway in tumor suppression and emphasizing the need for effective chemoprevention in these high-risk patients. Because the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) is a potent chemopreventive agent, we tested its efficacy in a highly relevant mouse model of BRCA1-mutated breast cancer. Beginning at 12 weeks of age, Brca1(Co/Co); MMTV-Cre;p53(+/-) mice were fed powdered control diet or diet containing CDDO-Me (50 mg/kg diet). CDDO-Me significantly (P < 0.05) delayed tumor development in the Brca1-mutated mice by an average of 5.2 weeks. We also observed that levels of ErbB2, p-ErbB2, and cyclin D1 increased in a time-dependent manner in the mammary glands in Brca1-deficient mice, and CDDO-Me inhibited the constitutive phosphorylation of ErbB2 in tumor tissues from these mice. In BRCA1-deficient cell lines, the triterpenoids directly interacted with ErbB2, decreased constitutive phosphorylation of ErbB2, inhibited proliferation, and induced G(0)-G(1) arrest. These results suggest that CDDO-Me has the potential to prevent BRCA1-mutated breast cancer.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Kim
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics*; D002453:Cell Cycle; D005260:Female; D019398:Genes, BRCA1; D016158:Genes, p53; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D009154:Mutation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D019313:BRCA1 Protein; D009828:Oleanolic Acid; D018719:Erb-b2 Receptor Tyrosine Kinases; C445068:bardoxolone methyl