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: Eun-Hee Kim, Chuxia Deng, Michael B Sporn, Darlene B Royce, Renee Risingsong, Charlotte R Williams, Karen T Liby
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 5 Issue 1 Pg. 89-97 (Jan 2012) ISSN: 1940-6215 [Electronic] United States
• PMID: 21933912 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Anticarcinogenic Agents
• BRCA1 Protein
• Oleanolic Acid
• bardoxolone methyl
• Receptor, ErbB-2

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• BRCA1 Protein (genetics)
• Cell Cycle
• Female
• Genes, BRCA1
• Genes, p53
• Mammary Neoplasms, Animal (genetics, prevention & control)
• Mice
• Mutation
• Oleanolic Acid (analogs & derivatives, pharmacology)
• Phosphorylation
• Receptor, ErbB-2 (metabolism)