Changes in biomarkers of estrogen receptor and growth factor signaling

Previously we have shown that MCF-7 human breast tumor growth is stimulated after prolonged treatment with dietary soy protein isolate (SPI). However, the effects are attenuated when SPI is combined with flaxseed (FS). This study determined the changes that occur in tumor growth biomarkers, after both short and long-term treatment with SPI, FS or their combination, to help identify signaling pathways potentially involved in SPI-stimulated tumor growth. Ovariectomized mice with established MCF-7 tumors were fed basal diet (control), 20%SPI, 10%FS, or SPI + FS for 2 or 25 weeks. After 2 weeks, there were no differences in tumor size, however, compared with control, SPI-treated tumors had higher IGF-IR and cyclin D1 while FS and SPI + FS-fed mice had lower pMAPK expression. After 25 weeks, SPI-treated tumors were larger, had higher proliferation, ER, cyclin D1, IGF-IR, and pMAPK and lower ER and HER2 levels. When combined with FS, however, the effects on these tumor biomarkers induced by SPI were attenuated. This study demonstrates that SPI and FS differently modulate tumor biomarkers of estrogen and growth factor signaling pathways, after both short- and long-term treatment, which may indicate a role of these pathways in the tumor stimulatory effects of SPI and the tumor inhibitory effects of FS. (Author's Abstract)
MCF-7 human breast tumor xenografts in require estrogen, acting through the estrogen receptor (ER), to stimulate tumor growth. Once mice are deprived of estrogen, through ovariectomy or administered anti-estrogens tumors regress. Two phytoestrogen-rich diets, soy protein isolate (SPI) and flaxseed (FS), alone and in combination, did not stimulate the growth of established MCF-7 tumors during the first few weeks of estrogen deprivation. However, after prolonged estrogen deprivation, continuous treatment with SPI induced the growth of MCF-7 tumors, while treatment with FS did not. Furthermore, when FS and SPI were combined, the tumor stimulatory effect of SPI was negated. This study was conducted to determine the changes in the tumor biomarkers after 2 weeks and after 25 weeks of treatment with SPI, FS and their combination. Tumor biomarkers measured were involved in cell proliferation, and ER and growth factor signaling. Identifying treatment-induced changes in certain biomarkers
may help identify potential mechanistic pathways involved in SPI-stimulated tumor growth, and how FS attenuates that growth. Biomarkers of cell proliferation and IGF-1R signaling were enhanced after 2 weeks of treatment in the tumors treated with SPI.  After 25 weeks of treatment, tumor cyclin D1 and IGF-1R continued to be elevated in the SPI tumors, in addition to Ki-67 LI, ER, and pMAPK.  Unlike SPI, FS did not show any tumor stimulatory effect on established MCF-7 tumors during both short- and long-term treatment periods. The mammalian lignans, enterolactone and enterodiol, produced from metabolism of FS plant lignans by intestinal microbiota have been shown to induce weak estrogenic effects on MCF-7 cells in vitro FS-fed mice, which had the lowest tumor cell proliferation after the short-term treatment period, also had decreased tumor pMAPK levels compared to NEG group, demonstrating an early tumor inhibitory effect.  Other components of FS (i.e. high n-3 fatty acids levels) in addition to plant lignans may be involved in reducing growth factor signaling in tumors and the in vivo interactive effects of these isolated components should be further investigated. Although this study does not provide definitive mechanisms of SPI and FS action, it helps to identify potential cell signaling pathways involved in their effects on tumor growth which need further exploration. (Editor's comments)