Tamoxifen and Flaxseed Alter Angiogenesis Regulators
Tamoxifen and Flaxseed Alter Angiogenesis Regulators
Authors: Nilsson Aberg, U.W. Saarinen, N. Abrahamsson, A. Nurmi, T. Engblom, S. Dabrosin, C.
Publication Name: PLoS One
Publication Details: Volume 6; Number 9; Pages e25720
The incidence of breast cancer is increasing in the Western world and there is an urgent need for studies of the mechanisms of sex steroids in order to develop novel preventive strategies. Diet modifications may be among the means for breast cancer prevention. Angiogenesis, key in tumor progression, is regulated by the balance between pro- and anti-angiogenic factors, which are controlled in the extracellular space. Sampling of these molecules at their bioactive compartment is therefore needed. The aims of this study were to explore if tamoxifen, one of the most used anti-estrogen treatments for breast cancer affected some of the most important endogenous angiogenesis regulators, vascular endothelial growth factor (VEGF), angiogenin, and endostatin in normal breast tissue in vivo and if a diet supplementation with flaxseed had similar effects as tamoxifen in the breast. Microdialysis was used for in situ sampling of extracellular proteins in normal breast tissue of women before and after six weeks of tamoxifen treatment or before and after addition of 25 g/day of ground flaxseed to the diet or in control women. We show significant correlations between estradiol and levels of VEGF, angiogenin, and endostatin in vivo, which was verified in ex vivo breast tissue culture. Moreover, tamoxifen decreased the levels of VEGF and angiogenin in the breast whereas endostatin increased significantly. Flaxseed did not alter VEGF or angiogenin levels but similar to tamoxifen the levels of endostatin increased significantly. We conclude that one of the mechanisms of tamoxifen in normal breast tissue include tipping of the angiogenic balance into an anti angiogenic state and that flaxseed has limited effects on the pro angiogenic factors whereas the anti angiogenic endostatin may be modified by diet. Further studies of diet modifications for breast cancer prevention are warranted. (Authors abstract)
Long term exposure to sex steroids such as estradiol and/or progesterone increases the risk of breast cancer. Angiogenesis is a key factor in tumor development and progression. One key angiogenic factor, vascular endothelial growth factor (VEGF), has been shown to be estrogen regulated in normal breast tissue and in breast cancer. Another potent proangiogenic factor is angiogenin a 14.2 kD polypeptide member of the RNase A superfamily. This research group has shown that angiogenin is estrogen regulated in a similar fashion as VEGF in normal breast tissue and experimental breast cancer. Endostatin is one important endogenous anti-angiogenic protein and may also down-regulate the VEGF/VEGFR signaling pathway. This group has also shown that estradiol down-regulates and tamoxifen up-regulates endostatin generation in experimental breast cancer. The objective of the present study was to determine if a diet of flaxseed or treatment with tamoxifen affected potent angiogenic regulators in normal human breast tissue in vivo. The results showed that endostatin, one of the most potent endogenous angiogenesis inhibitor, exhibited a negative correlation with estradiol in normal human breast tissue in situ. Tamoxifen increased the endostatin levels both in women in vivo and in cultured breast biopsies. In a similar fashion as tamoxifen, a diet of flaxseed to healthy premenopausal women increased the extracellular endostatin in breast tissue significantly. Tamoxifen significantly decreased the levels of VEGF and angiogenin in normal breast tissue both in microdialysates of women and in media of cultured breast tissue biopsies. A diet of flaxseed did not alter VEGF or angiogenin in the breast. This research group has also shown that a diet of 10% flaxseed to mice with estrogen dependent breast cancer explants reduces growth and angiogenesis by affecting angiogenesis regulators including VEGF. The present data did not show any effects of VEGF levels in breast tissue after the addition of flaxseed to the diet. The difference compared with the animal data, where VEGF levels decreased by flaxseed, may be a difference of cancerous tissue versus normal tissue. In animal studies, the amount of flaxseed added to the diet equates approximately 10% of the daily caloric intake while in women 25 g of ground flaxseed is less than 5% of the total calorie intake. There are several metabolically active components in flaxseed and it has been reported that flaxseed may affect estrogen metabolism in postmenopausal women. in this study no differences in estradiol and/or progesterone levels after flaxseed ingestion in the women nor were significant correlations between serum levels of secoisolariciresinol, enterodiol, enterolactone or the total enterolignan levels and endostatin in breast tissue noted. This may suggest that there is no strong dose-response relationship with endostatin and lignans, or the cohort was too small to detect a possible relationship or, that other component(s) in flaxseed, not measured may modulate endostatin in breast tissue. In summary, this study showed that the addition of 25 grams of ground flaxseed to healthy volunteers during one menstrual cycle did not affect the levels of angiogenin and VEGF in normal breast tissue but increased the levels of endostatin in a similar fashion as tamoxifen. A diet modification with flaxseed for one menstrual cycle does not seem to be equally powerful as tamoxifen in tipping the angiogenic balance towards angiogenesis inhibition in normal breast tissue. Further studies of diet alterations of a longer duration for elucidating effects on normal breast tissue for breast cancer prevention are warranted. (Editors comments)