The inhibitory effect of flaxseed on the growth and metastasis of estrogen receptor negative human breast cancer xenografts is attributed to both its lignan and oil components Linda Wang, Jianmin Chen and Lilian U. Thompson * Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, CanadaOur previous studies have shown that dietary flaxseed (FS) can reduce the growth and metastasis of human estrogen receptor negative (ER-) breast cancer in nude mice. The aims of our study were to determine (i) whether the tumor inhibitory effect of FS was due to its oil (FO), lignan secoisolariciresinol diglycoside (SDG), or both components, and (ii) whether the effect on tumor growth was related to increased lipid peroxidation. Athymic nude mice were orthotopically injected with ER-breast cancer cells (MDA-MB-435) and 8 weeks later were fed either the basal diet (BD) or BD supplemented with 10% FS, SDG, FO, or combined SDG and FO (SDG 1 FO) for 6 weeks. The SDG and FO levels were equivalent to the amounts in the 10% FS. Compared to the BD group, the tumor growth rate was significantly lower (p < 0.05) in the FS, FO, and SDG 1 FO groups, in concordance with decreased cell proliferation and increased apoptosis; however, these did not significantly relate to the lipid peroxidation, indexed as malonaldehyde (MDA), in the primary tumors. Lung metastasis incidence was reduced (16-70%) by all treatments, significantly in the FS and SDG 1 FO groups. The distant lymph node metastasis was significantly decreased (52%) only in the FO group. Although the total metastasis incidence was lowered (42%) significantly only in the SDG 1 FO group, all treatment groups did not differ significantly. In conclusion, FS reduced the growth and metastasis of established ER-human breast cancer in part due to its lignan and FO components, and not to lipid peroxidation. Previous studies have shown that the n-3 fatty acid, a-linolenic acid (ALA), as well as its metabolites, eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), and secoisolariciresinol diglycoside (SDG), the precursor to the mammalian lignans, enterolactone (EL) and enterodiol (ED), can inhibit the various stages of mammary carcinogenesis.1-4 Flaxseed (FS) contains the highest level of SDG, with values 75-800 times those in other plant foods, 5 and is also the richest source of ALA, 6 suggesting that it may be protective against mammary cancer.Dietary supplementation of 5 or 10% FS indeed has been shown to inhibit the initiation and early and late promotion stages of mammary carcinogenesis in carcinogen-treated rats.7-9 FS at 10% level has also been shown to inhibit the growth of both human estrogen receptor positive (ER1) MCF-7 and ER negative (ER-) MDA-MB-435 breast cancer xenografts in nude mice.10,11 Furthermore, spontaneous metastasis has been reduced by feeding mice with 10% FS diet when ER tumors are already established. 11,12 In carcinogen-treated rats, reduction in established tumor growth has been attributed to both the SDG and oil components of ...