Key Findings:
Flaxseed can reduce the mammary tumor development when it is given to carcinogen-treated rats at either the preinitiation or early or late promotion stages of carcinogenesis. FS also can inhibit the growth and metastasis of human estrogen receptor (ER) negative breast cancer (MDA-MB-435) in athymic mice, reduce the tumor cell proliferation and human epidermal growth factor receptor 2 (HER2) expression, and increase apoptosis in breast cancer patients. A diet with10% FS enhances the tumor inhibitory effect of tamoxifen (TAM) at high circulating E2 level and attenuates the tumor-stimulating effect of TAM at low E2 level in ovariectomized (OVX) athymic mice with established ER positive (ER+) human breast cancer (MCF-7). In this study, a tumor regrowth pattern was observed in the TAM group. FS had no tumor-inducing effect even in the longer term and can dose-dependently attenuate the tumor regrowth induced by TAM, with FS at 10% level having a greater effect. The inhibitory effect of FS on TAM-induced tumor regrowth may be in part due to down regulation of the expression of receptors in estrogen-related and signal transduction pathways.
ABSTRACT:
Our previous short-term study has shown that 10% flaxseed (FS) inhibits the growth of human estrogen dependent estrogen receptor positive breast tumors (MCF-7) xenografts in ovariectomized (OVX) athymic mice and enhances the tumor inhibitory effect of tamoxifen (TAM). This study determined the long-term effect of 5% and 10% FS, with or without TAM, on the growth of MCF-7 xenografts in athymic mice and the potential mechanisms of actions. OVX mice with established MCF-7 tumors were treated with basal diet (control), 5% FS (5FS), 10% FS (10FS), and TAM (5 mg/pellet, 60-day release), alone or in combination, for 16 wk without estrogen supplementation. Tumor growth was monitored weekly. At sacrifice, the tumors were analyzed by immunohistochemistry for cell proliferation, apoptosis, and expression of estrogen-related genes and signal transduction pathways. Both 5FS and 10FS regressed the pretreatment tumor size by over 90% similar to control. TAM initially regressed the tumors but then induced a regrowth; thus, only a final 6% reduction from pretreatment tumor size was achieved, which was attenuated by combining TAM with 10FS but not with 5FS. TAM combined with 10FS regressed tumors to 55% of pretreatment tumor size due to decreased cell proliferation and increased apoptosis. The expressions of cyclin D1, estrogen receptor α, human epidermal growth factor receptor 2, and insulin-like growth factor I receptor in the TAM group were significantly reduced when TAM was combined with 5FS or 10FS. In conclusion, after long-term treatment, FS did not stimulate tumor growth and combined with TAM, regressed tumor size in part due to downregulation of the expression of estrogen-related gene products and signal transduction pathways.
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