Flaxseed cotyledon fraction reduces tumour growth and sensitises tamoxifen treatment of human breast cancer xenograft (MCF-7) in athymic mice

January 1, 2011 Human Health and Nutrition Data 0 Comments

Flaxseed cotyledon fraction reduces tumour growth and sensitises tamoxifen treatment of human breast cancer xenograft (MCF-7) in athymic mice

Year: 2011
Authors: Chen, J. Saggar, J.K. Corey, P. Thompson, L.U.
Publication Name: Brit. J. Nutr.
Publication Details: Vol. 105; No. 3; Pages 1 – 9


Dietary flaxseed (FS) inhibited the growth of human breast tumours and enhanced the effectiveness of tamoxifen (TAM) in athymic mice with low oestradiol (E2) levels. The present study determined whether the n-3 fatty acid-rich cotyledon fraction of FS (FC), alone or in combination with TAM, has a similar effect and thus can substitute for FS. In a 2×2 factorial design, ovariectomised mice with established oestrogen receptor (ER)-positive breast tumours (MCF-7) were treated as follows: groups 1 and 2 were fed the basal diet (BD, control) and FC diet (82 g FC/kg), respectively. Groups 3 and 4 with TAM implants (5 mg) were fed the BD and FC diet, respectively. At 8 weeks post-treatment, mice were euthanised, and tumours were analysed by immunohistochemistry and real-time PCR. BD, FC and FC/TAM groups significantly decreased tumour area, but the TAM group did not. Tumour regression in the FC/TAM group was greater compared to the TAM group. FC lowered cell proliferation but had no effect on apoptosis; the opposite was observed with TAM. FC suppressed mRNA expressions of pS2 and insulin-like growth factor 1 receptor (IGF-1R) and protein expressions of ER a, phospho-specific ERa, human epidermal growth factor receptor 2 (HER2), phospho-specific HER2 (pHER2) and amplified in breast 1 (AIB1), while TAM up-regulated mRNA expressions of Bcl2, progesterone receptor and IGF-1R and protein expression of pHER2, and down-regulated ER b mRNA. FC modulated the effect of TAM on tumour growth biomarkers. In conclusion, FC reduced the growth of ER� human breast tumours at low circulating E2, alone and combined with TAM, in part through modulation of ER2 and growth factor-mediated signalling pathways; it may substitute for FS in increasing the effectiveness of TAM. (Author's Abstract)
Flaxseed (FS) is of interest in cancer research because it contains two major bioactive anti-cancer components, FS oil (FO) high in the omega 3 fatty acid, alpha-linolenic acid (ALA) and plant lignans, primarily secoisolariciresinol diglycoside (SDG) that can be metabolised by gut microbiota into mammalian lignans, enterodiol and enterolactone. Both enterodiol and enterolactone have weak oestrogenic or anti-oestrogenic activities due to their chemical structure which is similar to oestradiol (E2). FS can be mechanically processed to yield two fractions: the inner cotyledon fraction (FC), which represents 72�83% of the whole seed, and is rich in ALA but poor in lignan and the outside hull fraction, which represents 17�28% of the seed, and is rich in lignan content but low in ALA. Previous research by this group have shown that FS can increase the effectiveness of tamoxifen (TAM) treatment by inhibiting tumour growth in ovariectomised athymic mice with established ER beta – human breast cancer (MCF-7) at high or low circulating E2 concentration. Both the FO and lignan components of FS are responsible for this effect, but FO exhibits a stronger effect than lignan when combined with
TAM treatment.  It is unknown whether the ALA-rich FC fraction, also containing SDG, can similarly increase the effectiveness of TAM, and what may be the underlying mechanisms. This study aimed to determine the effect of FC, alone or in combination with TAM, on the growth of human breast tumour (MCF-7) in athymic mice with low circulating E2 levels, and to explore its potential mechanisms by investigating its effect on the expression of biomarkers in ER 2 and growth factor-mediated pathways. The results showed that, after removal of the E2 pellet to reduce circulating E2 to simulate the postmenopausal situation, established MCF-7 tumours in the BD, FC and FC/TAM groups, but not in the TAM group, significantly regressed in size. Dietary FC, at the level present in 10% FS, alone or combined with TAM treatment, did not promote tumour growth. The findings suggest that FC acted in part through down-regulation of ER 2 and growth factor-mediated signalling pathways. Further it was shown that FC has similar
effect to diets supplemented with whole FS or pure FO, when used either alone or combined with TAM. Thus, the FC at levels equivalent to that in 10% FS diet may potentially be consumed as an alternative to FS or FO. although of a short duration, the research also indicated that TAM treatment overall exhibited higher oestrogenicity in some biomarkers, such as uterus weight and expression of ER-beta and progesterone receptor. TAM alone also did not significantly regress the tumour size over the treatment period. However, the FC diet combined with TAM treatment induced significant tumour regression, and FC showed overall effect in decreasing the expression of oestrogen-related biomarkers, such as ER-alpha and phospho-specific ER-alpha proteins, pS2 mRNA and AIB1 protein. And, the FC/TAM treatment had a tendency to interactively reduce the uterine weight. FC was also shown to improve the responsiveness of TAM in reducing tumour growth through, at least in part, the down-regulation of HER2 and IGF-1R expression and the activation of the MAPK and Akt cascade. In summary, FC effectively reduced the growth of ER-beta human breast tumours at low circulating levels of E2. It enhanced the regression of TAM-treated tumours and, alone or combined with TAM treatment, reduced cell proliferation and increased apoptosis in part through modulation of ER 2 and growth factor mediated signalling pathways. (Editor's comments)

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