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

Key Findings:

Enterodiol and enterolactone derived from SDG have weak estrogenic or anti-estrogenic activities due to their chemical structure which is similar to estradiol (E2). Whether the ALA-rich inner cotyledon fraction (FC) fraction, also containing SDG, can increase the effectiveness of the breast cancer drug tamoxifen (TAM) was investigated. Established human breast tumour (MCF-7) in athymic mice significantly regressed in size in the control, FC and FC/TAM groups, but not in the TAM group. 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. FC showed overall effect in decreasing the expression of estrogen-related biomarkers, such as ER-alpha and phospho-specific ER-alpha proteins, pS2 mRNA and AIB1 protein. The responsiveness of TAM in reducing tumour growth was improved by FC through down-regulation of HER2 and IGF-1R expression and the activation of the MAPK and Akt cascade.

ABSTRACT:

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+ 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)