Dietary flaxseed lignan or oil combined with tamoxifen
Dietary flaxseed lignan or oil combined with tamoxifen
Year: 2010
Authors: Saggar, J.K. Chen, J. Corey, P. Thompson, L.U.
Publication Name: Mol.Nutr.Food Res.
Publication Details: Vol 54; Pages 415-425.
Abstract:
This study aimed to elucidate which component of flaxseed, i.e. secoisolariciresinol diglucoside (SDG) lignan or flaxseed oil (FO), makes tamoxifen (TAM) more effective in reducing growth of established estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels, and potential mechanisms of action. In a 22 factorial design, ovariectomized athymic mice with established tumors were treated for 8 wk with TAM together with basal diet (control), or basal diet supplemented with SDG (1 g/kg diet), FO (38.5 g/kg diet), or combined SDG and FO. SDG and FO were at levels in 10% flaxseed diet. Palpable tumors were monitored and after animal sacrifice, analyzed for cell proliferation, apoptosis, ER-mediated (ER-a, ER-beta, trefoil factor 1, cyclin D1, progesterone receptor, AIBI), growth factor-mediated (epidermal growth factor receptor, human epidermal growth factor receptor-2, insulin-like growth factor receptor-1, phosphorylated mitogen activated protein kinase, PAKT, BCL2) signaling pathways and
angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways. (Author's Abstract)
Tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is the most commonly prescribed drug for estrogen receptor positive (ER1) breast cancer. Its side-effects
include the development of menopausal-like symptoms, an increased risk for endometrial cancer, and after prolonged treatment, TAM resistance, and tumor re-grow. Flaxseed contains both lignans and oil rich in the n-3 fatty acid, alpha-linolenic acid (ALA). The predominant lignan in FS is secoisolariciresinol diglucoside (SDG), which is converted to the active mammalian lignans enterolactone (ENL) and enterodiol (END) by bacteria in the human and animal colon. END, ENL, and ALA have all been suggested to reduce cancer risk. The lignans may bind to the ER in a similar fashion as estradiol (E2) and TAM, and exert estrogenic as well as anti-estrogenic effects. FS and the mammalian lignans can alter E2 metabolism and bioavailability, and action of the ER on ER-dependent gene transcription. The objective of this study was to elucidate the component(s) of FS responsible for its anti-cancer effect and their potential mechanisms of action when combined with TAM treatment, with specific focus on the ER- and growth factor- mediated signaling pathways. The results demonstrated in athymic mice with low circulating levels of estrogen mimicking the post-menopausal situation, that TAM, alone or in combination with SDG, FO, or combined SDG and FO, can reduce the growth of established ER1 human breast tumors (MCF-7). However, FO gave the strongest effect in reducing the palpable tumor size of TAM treated tumors. FO and SDG combined with TAM also reduced the cell proliferation and increased the apoptosis but TAM+FO had a stronger effect in increasing apoptosis. Only SDG, without or with FO, induced lower expression of AIB1 protein, a co-activator of ER, indicating that SDG may exert a stronger modulating effect than FO on the ER signaling pathway. Compared with the TAM control, the treatments did not induce significantly higher expression of the estrogen target biomarkers, suggesting that there is no synergistic action of these treatments with TAM to induce estrogenic effect; this is desirable for breast cancer patients currently having TAM treatment and consuming these compounds. In this study, compared with TAM treatment alone (control), TAM combined with SDG or FO significantly reduced the mRNA expressions of IGF-1R and BCl2 and the protein expressions of HER2, PHER2, and PMAPK. In addition, SDG has significant overall effect in reducing EGFR mRNA while FO tends to have an overall effect in reducing HER2 mRNA expression. PAKT was reduced although not significantly. All these changes in gene and protein expressions indicate that SDG and particularly FO can strengthen the TAM effectiveness in part through down regulation of the signaling of growth factors IGF-1R, HER2, and EGFR expressions, which are known to interact and possibly also through decreased cross-talk between ER signaling and growth factor signaling, which then led to reduced downstream activation, particularly of MAPK, and decreased cell proliferation and increased apoptosis. Definitive recommendations on the use of FS, SDG, or FO as complementary treatment with TAM will depend on the results of future clinical trials testing their effects on breast cancer patients. (Editor's Comments)
angiogenesis (vascular endothelial growth factor). All treatments reduced the growth of TAM treated tumors by reducing cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways with FO having the greatest effect in increasing apoptosis compared with TAM treatment alone. SDG and FO reduced the growth of TAM-treated tumors but FO was more effective. The mechanisms involve both the ER- and growth factor-signaling pathways. (Author's Abstract)
Tamoxifen (TAM), a selective estrogen receptor (ER) modulator, is the most commonly prescribed drug for estrogen receptor positive (ER1) breast cancer. Its side-effects
include the development of menopausal-like symptoms, an increased risk for endometrial cancer, and after prolonged treatment, TAM resistance, and tumor re-grow. Flaxseed contains both lignans and oil rich in the n-3 fatty acid, alpha-linolenic acid (ALA). The predominant lignan in FS is secoisolariciresinol diglucoside (SDG), which is converted to the active mammalian lignans enterolactone (ENL) and enterodiol (END) by bacteria in the human and animal colon. END, ENL, and ALA have all been suggested to reduce cancer risk. The lignans may bind to the ER in a similar fashion as estradiol (E2) and TAM, and exert estrogenic as well as anti-estrogenic effects. FS and the mammalian lignans can alter E2 metabolism and bioavailability, and action of the ER on ER-dependent gene transcription. The objective of this study was to elucidate the component(s) of FS responsible for its anti-cancer effect and their potential mechanisms of action when combined with TAM treatment, with specific focus on the ER- and growth factor- mediated signaling pathways. The results demonstrated in athymic mice with low circulating levels of estrogen mimicking the post-menopausal situation, that TAM, alone or in combination with SDG, FO, or combined SDG and FO, can reduce the growth of established ER1 human breast tumors (MCF-7). However, FO gave the strongest effect in reducing the palpable tumor size of TAM treated tumors. FO and SDG combined with TAM also reduced the cell proliferation and increased the apoptosis but TAM+FO had a stronger effect in increasing apoptosis. Only SDG, without or with FO, induced lower expression of AIB1 protein, a co-activator of ER, indicating that SDG may exert a stronger modulating effect than FO on the ER signaling pathway. Compared with the TAM control, the treatments did not induce significantly higher expression of the estrogen target biomarkers, suggesting that there is no synergistic action of these treatments with TAM to induce estrogenic effect; this is desirable for breast cancer patients currently having TAM treatment and consuming these compounds. In this study, compared with TAM treatment alone (control), TAM combined with SDG or FO significantly reduced the mRNA expressions of IGF-1R and BCl2 and the protein expressions of HER2, PHER2, and PMAPK. In addition, SDG has significant overall effect in reducing EGFR mRNA while FO tends to have an overall effect in reducing HER2 mRNA expression. PAKT was reduced although not significantly. All these changes in gene and protein expressions indicate that SDG and particularly FO can strengthen the TAM effectiveness in part through down regulation of the signaling of growth factors IGF-1R, HER2, and EGFR expressions, which are known to interact and possibly also through decreased cross-talk between ER signaling and growth factor signaling, which then led to reduced downstream activation, particularly of MAPK, and decreased cell proliferation and increased apoptosis. Definitive recommendations on the use of FS, SDG, or FO as complementary treatment with TAM will depend on the results of future clinical trials testing their effects on breast cancer patients. (Editor's Comments)
