Abstract
BACKGROUND: Anti-oestrogens such as tamoxifen, decrease the risk of breast cancer but are unsuitable for prevention because of their side-effects. Diet modifications may be a breast cancer prevention strategy. Here, we investigated if a diet addition of flaxseed, which can be converted to the phytoestrogen enterolactone by the gut microbiota, exhibited similar effects as tamoxifen on normal human breast tissue in vivo, with special emphasis on inflammatory mediators implicated in cancer progression. SUBJECTS: A total of 28 postmenopausal women were included. Thirteen women added 25 g of ground flaxseed per day and 15 were treated with tamoxifen as an adjuvant for early breast cancer for 6 weeks. Microdialysis of normal breast tissue and, as a control, in subcutaneous abdominal fat was performed for sampling of extracellular proteins in vivo before and after exposures.
RESULTS: Enterolactone levels increased significantly after flaxseed. IL-1Ra and IL-1Ra/IL-1β ratio in the breast increased in a similar fashion after the two different treatments. Flaxseed also increased breast specific levels of IL-1RT2, IL-18 and sST2 and an overall increase of MMP-9. These changes correlated significantly with enterolactone levels. Tamoxifen decreased breast tissue levels of IL-8 and IL-18. None of the treatments induced any changes of IL-1β, IL-1RT1, IL-18BP, IL-33, IL-6, IL-6RA, MMP-1, MMP-2 and MMP-3. CONCLUSIONS: We conclude that dietary flaxseed and tamoxifen exert both similar and different effects, as listed above, on normal breast tissue in vivo and that a relatively modest diet change can induce significant effects on the breast microenvironment.
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Key Points
Chemoprevention of breast cancer with pharmacological anti-oestrogen therapies such as tamoxifen leads to a 30–50% risk reduction, but these treatments are associated with severe side-effects such as thromboembolism, endometrial cancer and low quality of life. Matrix metalloproteases (MMPs) are key enzymes of remodelling processes including an activation of several pro-inflammatory cytokines. Dependent on these activities, MMPs have been associated with both pro- and anti-tumorigenic effects. The hypothesis here was that tamoxifen affects the inflammatory microenvironment in vivo and that a diet addition of flaxseed exhibited similar effects as tamoxifen on normal human breast tissue. Postmenopausal women were treated with tamoxifen or a dietary addition of 25 g of ground flaxseed/day for 6 weeks.
Both a dietary addition of flaxseed and tamoxifen affected the local inflammatory microenvironment in normal breast tissue in postmenopausal women. While similar alterations of IL-Ra and the ratio Il-1Ra/IL-1β were induced by the two treatments other members of the IL-1 family of cytokines were affected differently; after flaxseed ingestions, IL-1RT2, IL-18 and sST2 were significantly up-regulated whereas tamoxifen down-regulated IL-18. Additionally, tamoxifen decreased the levels of IL-8 and borderline significant increase of IL-6RA was detected after flaxseed ingestion. All the above-mentioned changes were tissue specific for normal breast tissue as no alterations were found in the reference tissue i.e., s.c. abdominal fat. Furthermore, flaxseed induced increased levels of MMP-9
both in the breast and s.c. fat. Serum enterolactone levels exhibited a significantly positive correlation with the increased proteins. The authors concluded that in some aspects a diet addition of flaxseed exhibits similar alterations in breast tissue as tamoxifen does, and that these changes can be interpreted as protective against breast cancer. In other aspects flaxseed and tamoxifen induce divergent effects, which can be both beneficial and detrimental for breast cancer initiation and progression. Before any conclusion can be made of these alteration further studies are needed. A relatively modest diet change can induce significant effects on normal human breast tissue in vivo and suggest that dietary interventions such as flaxseed supplementation can be included in breast cancer prevention trials.