Dietary flaxseed lignan or oil combined with tamoxifen treatment affects MCF-7 tumor growth through estrogen.

Key Findings:

Flaxseed secoisolariciresinol diglucoside (SDG), which is converted to the active mammalian lignans enterolactone (ENL) and enterodiol (END) as well as ALA have all been suggested to reduce cancer risk. Tamoxifen (TAM) is a selective estrogen receptor (ER) modulator and is used to treat estrogen receptor positive (ER1) breast cancer. In this work, compounds in flaxseed were when combined with TAM treatment, were evaluated for effects on the ER- and growth factor- mediated signaling pathways. In athymic mice with low circulating levels of estrogen (similar to the situation in post-menopause) TAM, alone or in combination with SDG, flaxseed oil (FO), or combined SDG and FO, can reduce the growth of established ER1 human breast tumors (MCF-7). 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. 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. The results show 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.

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)