Flaxseed Alone or in Combination with Tamoxifen Inhibits MCF-7 Breast Tumor Growth in Ovariectomized Athymic Mice with High Circulating Levels of Estrogen.

Key Findings:

Tamoxifen (TAM) protects against ERþ breast cancer by competing with estradiol (E2) for binding to the ER, thereby reducing E2-stimulated breast cancer growth but produces side effects from TAM treatment. Previous study in ovariectomized athymic mice with established ERþ human breast cancer (MCF-7) showed that 10% FS enhanced the tumor inhibitory effect of TAM at high circulating E2 level. This study demonstrated a greater inhibitory effect on the tumor growth induced by the combined FS-TAM treatment. The 5FS diet inhibited cancer growth when combined with TAM under high circulating levels of E2. The mechanisms by which FS alone exerts this inhibitory effect include decreasing cell proliferation and increasing apoptosis due to its antiestrogenic effect and ability to downregulate IGF-1 expression. An agonistic effect was induced when FS was combined with TAM, which may be attributed to the enhanced antiestrogenic effect and modulation of signal transduction pathways.

ABSTRACT:

Flaxseed (FS) is rich in mammalian lignan precursors and alinolenic acid, which have been suggested as having anticancer effects. Previous studies have shown that 10% FS inhibits the growth of human estrogen–dependent breast cancer (MCF-7) in athymic mice, and it enhances the inhibitory effect of tamoxifen (TAM). This study determined whether the effect of FS, alone or in combination with TAM, is dose dependent, and it explored the potential mechanism of action. Ovariectomized athymic mice with estradiol (E2) supplementation (1.7 mg/pellet, 60-day release) and established MCF-7 tumors were treated with basal diet control (0FS), 5% FS (5FS), 10% FS (10FS), and TAM (TAM/ 0FS; 5 mg/pellet, 60-day release), alone or in combination (TAM/ 5FS and TAM/10FS) for 8 weeks. Compared with control, 5FS and 10FS significantly inhibited tumor growth by 26% and 38%, respectively. TAM/0FS had an effect similar to the 10FS. TAM/ 5FS and TAM/10FS, respectively, induced significant 48% and 43% reductions in tumor size compared with 0FS, and 18% and 10% reductions compared with TAM/0FS. The relative uterine weight was significantly lower in all TAM groups compared with the control. The reduction of tumor growth resulted from decreased cell proliferation and increased cell apoptosis. TAM/5FS caused a significantly higher expression of estrogen receptor-a (ERa) compared with 5FS and TAM/0FS, whereas TAM/10FS had a higher ERa than 10FS and TAM/0FS. Compared with the control, progesterone receptor (PgR) expression was significantly reduced in all treatment groups, but insulin-like growth factor-1 (IGF-1) expression was reduced only by 10FS, TAM/5FS and TAM/10FS. Tumor cell proliferation was significantly positively associated with expression of PgR and IGF-1 and negatively associated with apoptosis and ERa. Apoptosis was only associated with ERa. In conclusion, FS inhibited MCF-7 tumor growth in a dose-dependent manner and enhanced the inhibitory effect of TAM due to the modulation of ER and growth factor signal transduction pathways.