Dietary depletion of vitamin E and vitamin A inhibits mammary tumor growth and metastasis in transgenic mice.

We showed previously that dietary antioxidant depletion enhances tumor reactive oxygen species (ROS) and apoptosis, resulting in a reduction in brain tumor size in the TgT(121) transgenic mouse model, a nonmetastatic tumor model. Here, in a transgenic mouse model of mammary tumorigenesis with defined rates of tumor growth and lung-targeted metastasis, we determined the ability of dietary antioxidant depletion to inhibit tumor growth and metastasis. Compared with control mice fed a standard diet, antioxidant-depleted mice exhibited tumor-targeted generation of ROS manifested by increased levels of oxidatively modified DNA/RNA (8-hydroxy-2'-deoxyguanine, 8-hydroxyguanine) and lipid peroxidation (4-hydroxy-2-nonenal) in primary and metastatic tumor foci. In addition to increased tumor-targeted ROS, the number of apoptotic cells was increased approximately 500% (P < 0.01) and terminal dUTP nucleotide DNA end-labeling-positive cells 200% (P < 0.01) in mice fed the antioxidant-depleted diet, whereas the percentage of tumor cells undergoing mitosis was >50% lower than in controls (P < 0.01). The proportional distribution of small (<1.5 cm) and large (greater than or equal to1.5 cm) primary mammary tumors differed. The mice fed the antioxidant-depleted diet had more small primary tumors (P < 0.05) and fewer large primary tumors (P < 0.05). Importantly, they also had fewer lung metastatic tumor foci compared with mice fed the control diet (4.5 +/- 1.3 vs. 15.8 +/- 8.5 foci/lung, P < 0.01). These findings may be important in understanding the role of dietary antioxidant vitamins in tumor growth and metastasis.