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Prevention and Treatment of Experimental Estrogen Receptor–Negative Mammary Carcinogenesis by the Synthetic Triterpenoid CDDO-Methyl Ester and the Rexinoid LG100268

Authors' Affiliations: ¹ Department of Pharmacology, Dartmouth Medical School; ² Department of Chemistry, Dartmouth College, Hanover, New Hamsphire; ³ Ligand Pharmaceuticals, Inc., San Diego, California; and ⁴ Multimedica IRCCS, Milan, Italy

Requests for reprints: Karen Liby, Department of Pharmacology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-6558; Fax: 603-650-1129; E-mail: karen.liby{at}dartmouth.edu.

Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)–negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice.

Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks.

Results: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKB in ER-negative breast cancer cells, whereas 268 blocked IKB degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo.

Conclusions: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.