Abstract
Breast cancer is the most common cancer among women in the United States. The incidence rates of breast cancer are no longer significantly declining, and approximately 40,000 women die from the disease each year. Hence, novel drugs are needed for the prevention and treatment of the disease. Synthetic triterpenoids are a promising new class of compounds with chemopreventive activity in a variety of preclinical cancer models. We tested 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 ER-negative breast cancer. In this mouse model, the polyoma-middle T (PyMT) oncoprotein drives carcinogenesis in the mammary gland. The developing tumors recapitulate key features of the human disease including significant infiltration of tumor-associated macrophages (TAM). Depletion of TAMs has been previously shown to delay tumor progression. PyMT 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 by an average of 4.3 weeks (P < 0.001) and overall survival by 5.2 weeks (P < 0.001). CDDO-Me significantly (P < 0.05) inhibited the infiltration of TAMs into mammary glands of PyMT mice along with levels of the chemokines CXCL12 and CCL2 in primary PyMT mammary tumor cells. Treatment with CDDO-Me also inhibited secretion of MMP-9 in primary tumor cells from PyMT mice and decreased proliferation of these cells by inhibiting cyclin D1 and decreasing phosphorylation of EGFR and STAT3, key breast cancer biomarkers. Thus, CDDO-Me delayed breast carcinogenesis via inhibition of TAM infiltration and by inhibition of key pathways in breast carcinogenesis. Taken together, these findings implicate CDDO-Me as a promising chemopreventive agent for ER-negative breast cancer via inhibition of TAM infiltration and diverse oncogenic pathways.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A103.
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