Article | Published:

Interventions and public health nutrition

Dietary flaxseed and tamoxifen affect the inflammatory microenvironment in vivo in normal human breast tissue of postmenopausal women

European Journal of Clinical Nutrition (2019) | Download Citation



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.


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.


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.


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2011;125:315–23.

  2. 2.

    Thompson LU, Boucher BA, Liu Z, Cotterchio M, Kreiger N. Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan. Nutr Cancer. 2006;54:184–201.

  3. 3.

    Pietinen P, Stumpf K, Mannisto S, Kataja V, Uusitupa M, Adlercreutz H. Serum enterolactone and risk of breast cancer: a case–control study in eastern Finland. Cancer Epidemiol Biomark Prev. 2001;10:339–44.

  4. 4.

    Olsen A, Knudsen KE, Thomsen BL, Loft S, Stripp C, Overvad K, et al. Plasma enterolactone and breast cancer incidence by estrogen receptor status. Cancer Epidemiol Biomark Prev. 2004;13:2084–9.

  5. 5.

    Saarinen NM, Power K, Chen J, Thompson LU. Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF-7 human breast cancer xenografts. Int J Cancer. 2006;119:925–31.

  6. 6.

    Bergman Jungestrom M, Thompson LU, Dabrosin C. Flaxseed and its lignans inhibit estradiol-induced growth, angiogenesis, and secretion of vascular endothelial growth factor in human breast cancer xenografts in vivo. Clin Cancer Res. 2007;13:1061–7.

  7. 7.

    Zaineddin AK, Vrieling A, Buck K, Becker S, Linseisen J, Flesch-Janys D, et al. Serum enterolactone and postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status. Int J Cancer. 2012;130:1401–10.

  8. 8.

    Seibold P, Vrieling A, Johnson TS, Buck K, Behrens S, Kaaks R, et al. Enterolactone concentrations and prognosis after postmenopausal breast cancer: assessment of effect modification and meta-analysis. Int J Cancer. 2014;135:923–33.

  9. 9.

    Lash TL, Fox MP, Westrup JL, Fink AK, Silliman RA. Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat. 2006;99:215–20.

  10. 10.

    Jaskulski S, Jung AY, Behrens S, Johnson T, Kaaks R, Thone K, et al. Circulating enterolactone concentrations and prognosis of postmenopausal breast cancer: Assessment of mediation by inflammatory markers. Int J Cancer. 2018;143:2698–708.

  11. 11.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

  12. 12.

    Mantovani A, Barajon I, Garlanda C. IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev. 2018;281:57–61.

  13. 13.

    Kantono M, Guo B. Inflammasomes and cancer: the dynamic role of the inflammasome in tumor development. Front Immunol. 2017;8:1132.

  14. 14.

    Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissiere F, Laune D, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res. 2007;9:R15.

  15. 15.

    Dethlefsen C, Hojfeldt G, Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat. 2013;138:657–64.

  16. 16.

    Singh JK, Simoes BM, Howell SJ, Farnie G, Clarke RB. Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells. Breast Cancer Res. 2013;15:210.

  17. 17.

    Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis. 2005;8:63–71.

  18. 18.

    Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295:2387–92.

  19. 19.

    Overall CM, Kleifeld O. Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer. 2006;6:227–39.

  20. 20.

    Bendrik C, Robertson J, Gauldie J, Dabrosin C. Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo. Cancer Res. 2008;68:3405–12.

  21. 21.

    Leifler KS, Svensson S, Abrahamsson A, Bendrik C, Robertson J, Gauldie J, et al. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J Immunol. 2013;190:4420–30.

  22. 22.

    Liotta LA, Stetler-Stevenson WG. Metalloproteinases and cancer invasion. Semin Cancer Biol. 1990;1:99–106.

  23. 23.

    Aberg UW, Saarinen N, Abrahamsson A, Nurmi T, Engblom S, Dabrosin C. Tamoxifen and flaxseed alter angiogenesis regulators in normal human breast tissue in vivo. PLoS ONE 2011;6:e25720.

  24. 24.

    Bendrik C, Dabrosin C. Estradiol increases IL-8 secretion of normal human breast tissue and breast cancer in vivo. J Immunol. 2009;182:371–8.

  25. 25.

    Dabrosin C. Increase of free insulin-like growth factor-1 in normal human breast in vivo late in the menstrual cycle. Breast Cancer Res Treat. 2003;80:193–8.

  26. 26.

    Dabrosin C. Increased extracellular local levels of estradiol in normal breast in vivo during the luteal phase of the menstrual cycle. J Endocrinol. 2005;187:103–8.

  27. 27.

    Dabrosin C. Microdialysis—an in vivo technique for studies of growth factors in breast cancer. Front Biosci. 2005;10:1329–35.

  28. 28.

    Dabrosin C. Sex steroid regulation of angiogenesis in breast tissue. Angiogenesis. 2005;8:127–36.

  29. 29.

    Garvin S, Dabrosin C. In vivo measurement of tumor estradiol and vascular endothelial growth factor in breast cancer patients. BMC Cancer. 2008;8:73.

  30. 30.

    Nilsson UW, Abrahamsson A, Dabrosin C. Angiogenin regulation by estradiol in breast tissue: tamoxifen inhibits angiogenin nuclear translocation and antiangiogenin therapy reduces breast cancer growth in vivo. Clin Cancer Res. 2010;16:3659–69.

  31. 31.

    Abrahamsson A, Dabrosin C. Tissue specific expression of extracellular microRNA in human breast cancers and normal human breast tissue in vivo. Oncotarget. 2015;6:22959–69.

  32. 32.

    Uehar M, Arai Y, Watanabe S, Adlercreutz H. Comparison of plasma and urinary phytoestrogens in Japanese and Finnish women by time-resolved fluoroimmunoassay. Biofactors. 2000;12:217–25.

  33. 33.

    Adlercreutz H, Wang GJ, Lapcik O, Hampl R, Wahala K, Makela T, et al. Time-resolved fluoroimmunoassay for plasma enterolactone. Anal Biochem. 1998;265:208–15.

  34. 34.

    Abrahamsson A, Morad V, Saarinen NM, Dabrosin C. Estradiol, tamoxifen, and flaxseed alter IL-1beta and IL-1Ra levels in normal human breast tissue in vivo. J Clin Endocrinol Metab. 2012;97:E2044–54.

  35. 35.

    Lindahl G, Saarinen N, Abrahamsson A, Dabrosin C. Tamoxifen, flaxseed, and the lignan enterolactone increase stroma- and cancer cell-derived IL-1Ra and decrease tumor angiogenesis in estrogen-dependent breast cancer. Cancer Res. 2011;71:51–60.

  36. 36.

    Morad V, Abrahamsson A, Kjolhede P, Dabrosin C. Adipokines and vascular endothelial growth factor in normal human breast tissue in vivo—correlations and attenuation by dietary flaxseed. J Mammary Gland Biol Neoplasia. 2016;21:69–76.

  37. 37.

    Svensson S, Abrahamsson A, Rodriguez GV, Olsson AK, Jensen L, Cao Y, et al. CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clin Cancer Res. 2015;21:3794–805.

  38. 38.

    Vazquez Rodriguez G, Abrahamsson A, Jensen LD, Dabrosin C. Estradiol promotes breast cancer cell migration via recruitment and activation of neutrophils. Cancer Immunol Res. 2017;5:234–47.

  39. 39.

    Possemiers S, Bolca S, Eeckhaut E, Depypere H, Verstraete W. Metabolism of isoflavones, lignans and prenylflavonoids by intestinal bacteria: producer phenotyping and relation with intestinal community. FEMS Microbiol Ecol. 2007;61:372–83.

  40. 40.

    Landete JM, Arques J, Medina M, Gaya P, de Las Rivas B, Munoz R. Bioactivation of phytoestrogens: intestinal bacteria and health. Crit Rev Food Sci Nutr. 2016;56:1826–43.

  41. 41.

    Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, et al. Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour–host interactions. Eur J Cancer. 2006;42:751–9.

  42. 42.

    Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA. 2003;100:2645–50.

  43. 43.

    Bar D, Apte RN, Voronov E, Dinarello CA, Cohen S. A continuous delivery system of IL-1 receptor antagonist reduces angiogenesis and inhibits tumor development. FASEB J. 2004;18:161–3.

  44. 44.

    Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The interleukin (IL)-1 cytokine family—balance between agonists and antagonists in inflammatory diseases. Cytokine. 2015;76:25–37.

  45. 45.

    Kaplanski G. Interleukin-18: biological properties and role in disease pathogenesis. Immunol Rev. 2018;281:138–53.

  46. 46.

    Aguiar MAN, Wanderley CWS, Nobre LMS, Alencar MRM, Saldanha M, Souza AM, et al. Interleukin-18 (IL-18) is equally expressed in inflammatory breast cancer and noninflammatory locally advanced breast cancer: a possible association with chemotherapy response. Asia Pac J Clin Oncol. 2018;14:e138–44.

  47. 47.

    Fabbi M, Carbotti G, Ferrini S. Context-dependent role of IL-18 in cancer biology and counter-regulation by IL-18BP. J Leukoc Biol. 2015;97:665–75.

  48. 48.

    Griesenauer B, Paczesny S. The ST2/IL-33 axis in immune cells during inflammatory diseases. Front Immunol. 2017;8:475.

  49. 49.

    Xiao P, Wan X, Cui B, Liu Y, Qiu C, Rong J, et al. Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells. Oncoimmunology. 2016;5:e1063772.

  50. 50.

    Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, et al. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 2014;141:125–39.

  51. 51.

    Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nature reviews. Clin Oncol. 2018;15:234–48.

  52. 52.

    Alfaro C, Sanmamed MF, Rodriguez-Ruiz ME, Teijeira A, Onate C, Gonzalez A, et al. Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat Rev. 2017;60:24–31.

  53. 53.

    Abrahamsson A, Rzepecka A, Romu T, Borga M, Leinhard OD, Lundberg P, et al. Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo. Oncoimmunology. 2016;5:e1229723.

  54. 54.

    Nilsson UW, Garvin S, Dabrosin C. MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat. 2007;102:253–61.

  55. 55.

    Abrahamsson A, Rzepecka A, Dabrosin C. Equal pro-inflammatory profiles of CCLs, CXCLs, and matrix metalloproteinases in the extracellular microenvironment in vivo in human dense breast tissue and breast cancer. Front Immunol. 2017;8:1994.

  56. 56.

    Zhu Y, Kawaguchi K, Kiyama R. Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors. PLoS ONE 2017;12:e0171390.

  57. 57.

    Mason JK, Thompson LU. Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer? Appl Physiol Nutr Metab. 2014;39:663–78.

Download references


The authors would like to thank RN Ann-Christine N Andersson at Linköping University Hospital for providing excellent assistance in recruiting the subjects.


This work was supported by grants to CD from the Swedish Cancer Society (2015/309), the Swedish Research Council (2013–2457), and ALF of Linköping University Hospital.

Author contributions

All authors collaborated on the study conception, study design, and data interpretation. CD and GL recruited the patients. CD performed all microdialysis experiments. AA and GL carried out sample preparation and Luminex and EIA analyses. All authors performed data analysis and drafted the manuscript. All authors read and approved the final version of the manuscript.

Author information


  1. Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

    • Gabriel Lindahl
    • , Annelie Abrahamsson
    •  & Charlotta Dabrosin


  1. Search for Gabriel Lindahl in:

  2. Search for Annelie Abrahamsson in:

  3. Search for Charlotta Dabrosin in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Charlotta Dabrosin.

About this article

Publication history