Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity

Abstract

Mechanisms underlying the chemopreventive effect of difluoromethylornithine (DFMO) on the development of mammary cancer were investigated utilizing the whey acidic protein promoter-T antigen transgenic mouse model of breast cancer progression. Mice were exposed to four different doses of DFMO in the diet (3.5, 4.9, 7.0 and 10 g/kg diet). Tumor latency was increased in a dosedependent manner. DFMO at the highest dose significantly delayed tumor onset (131 days as compared to 109 days in control unexposed mice, P ¼ 0.018). Analyses of preneoplastic mammary tissue collected 1 month after DFMO treatment demonstrated that DFMO (10 g/kg diet) significantly increased the ratio of apoptotic to proliferative indices (P ¼ 0.013) and significantly reduced the percentage of cells demonstrating nuclear localized cyclin D1 (P ¼ 0.013). Nuclear localizations of p27, p21 and Stat5a were not affected. Inhibitory effects of DFMO on cell growth and survival were lost as the cells progressed to cancer. In conclusion, the chemopreventive effects of DFMO on mammary cancer progression were mediated by changes in both apoptosis and cell proliferation in preneoplastic cells. Alterations in cyclin D1 activity in preneoplastic cells could represent an early biomarker of chemopreventive action and are consistent with a mechanistic role for cyclin D1 in progression of mammary cancer.

Polyamine depletion partially reduces the radiation-induced cell death via cell cycle delay mediated by thioredoxin

“…In most cells except for fibroblast cell lines, overexpression of cyclin D1 accelerates entry into the S phase, which is essential for the G 2 checkpoint, and thus is important for the modulation of radiation-induced cell death. The chemopreventive effect of DFMO on the proliferation of mammary cancer is known to be associated with decreased cyclin D1 activity (Li et al, 2003). DFMO-treated HT29 cells in our studies showed a reduction of cyclin D1 and an increase of HSP25, which is in accord with findings in other radiation-resistant cells.…”

Chemoprevention of B-Cell Lymphomas by Inhibition of the Myc Target Spermidine Synthase

“…Odc has been shown to be important for tumor development in mouse models of lymphoma, skin, prostate, breast, and colon cancer, and most recently, neuroblastoma (10,11,(20)(21)(22)(23)(24). In the Eμ-Myc mouse, treatment with the suicide Odc enzyme inhibitor DFMO reduced rates of proliferation of B cells and delayed lymphomagenesis significantly (11).…”