title: The synthetic triterpenoid CDDO-methyl ester delays estrogen receptor-negative mammary carcinogenesis in polyoma middle T mice.
abstract: Novel drugs are needed for the prevention and treatment of breast cancer. Synthetic triterpenoids are a promising new class of compounds with activity in a variety of preclinical cancer models. We tested activity of the methyl ester derivative of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me), in a relevant model of estrogen receptor-negative breast cancer, the polyoma-middle T (PyMT), in which the oncoprotein drives carcinogenesis. The developing tumors recapitulate key features of the human disease. Mice were fed CDDO-Me (50 mg/kg diet), starting at 4 weeks of age. CDDO-Me significantly increased the age of mice at onset of first tumor (P < 0.001) by an average of 4.3 weeks and overall survival (P < 0.001) by 5.2 weeks. The drug also inhibited the infiltration of tumor-associated macrophages into mammary glands of PyMT mice at 12 weeks of age and reduced levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with this multifunctional drug also inhibited secretion of matrix metalloproteinase-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of epidermal growth factor receptor and STAT3.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Tran
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.forename: Darlene
authors.initials: D
authors.lastname: Royce
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Karen
authors.initials: K
authors.lastname: Liby
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014315:Triterpenes / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016588:Anticarcinogenic Agents; D000952:Antigens, Polyomavirus Transforming; D011960:Receptors, Estrogen; D014315:Triterpenes; D009828:Oleanolic Acid; C445068:bardoxolone methyl