ABSTRACT

Our previous studies show that combined flaxseed (FS) and soy protein isolate (SPI), or their respective phytoestrogens (PEs), lignans (enterolactone (ENL) or enterodiol (END)) and isoflavone (GEN), can more effectively reduce estrogen receptor (ER) positive human breast cancer (BC) growth in ovariectomized (OVX) mice than with SPI or GEN alone. This study determined the potential mechanisms of action with regards to treatment-induced effects on signaling pathways involved in tumor growth. OVX mice with established MCF-7 tumors were fed the basal diet (BD) –E2 control, 20%SPI, 10%FS, or 20%SPI+10%FS for 2 weeks (short-term treatment) or 25 weeks (long-term treatment.) Tumors were analyzed by immunohistochemistry for proliferation (Ki67 labeling index (LI)), ERα, cyclin D1, and pMAPK. SPI slightly increased cyclin D1 at the short-term period but significantly increased Ki67, ERα, cyclin D1, and pMAPK compared to control at the long-term period. At 2 weeks, FS alone reduced Ki67 compared to SPI and SPI+FS and when combined with SPI, it significantly reduced pMAPK compared to –E2 and SPI, indicating an early tumor inhibitory effect. At 25 weeks, FS did not modulate biomarkers different from –E2 but when combined with SPI, it negated SPI effects on Ki67, cyclin D1, and pMAPK, suggesting a potential mechanism for its tumor inhibitory effect. In a similar study, GEN acted comparable to SPI, without significant effects on pMAPK. Unlike FS, ENL and END did not induce short-term effects suggesting other FS components may be responsible for FS effects. Overall, this study suggests that SPI and GEN induce its tumor promoting effects by acting through the ER and MAPK pathways to increase cyclin D1 and cell proliferation, while the lignans and FS do not. However, when SPI and FS are combined, ER and MAPK pathways are negated to decrease tumor growth.