Flaxseed (FS) is rich in mammalian
lignan precursors and
alpha-linolenic 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-alpha (
ERalpha) compared with 5FS and TAM/0FS, whereas TAM/10FS had a higher
ERalpha 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
ERalpha. Apoptosis was only associated with
ERalpha. 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.