Animal studies suggest that genistein and daidzein have an ability to prevent or reduce bone loss in a manner similar to synthetic estrogen due to increased beta versus alpha estrogen receptor (ER) binding (10). Both isoflavones may modulate bone remodeling through ERs by regulating target gene expression (50). Soy may also contribute to maintaining bone density by causing less calcium to be excreted in the urine (35).
Proposed mechanisms of soy’s cholesterol-lowering effect include phytoestrogen-induced hyperthyroid state and increased excretion of bile acids, which may enhance removal of LDL. Isoflavones may inhibit oxidation of LDL and may alter hepatic metabolism with enhanced removal of LDL and VLDL by hepatocytes (17). Serum lipids may also be regulated through modified transcription factor and downstream gene expression and by promoting antioxidant enzyme activity (51).
The phytochemicals in soybeans also exhibit anticarcinogenic activity, for which many mechanisms have been proposed. Genistein affects microRNA expression—targeted translation inhibitors for multiple proteins implicated in the regulation of various pathobiological processes in cancer (52). In addition, genistein demonstrated an anti-minichromosome maintenance (MCM) effect, a gene family frequently upregulated in various cancers and considered a promising anticancer drug target (53).
In breast cancer, genistein acts as an agonist to estrogen receptor (ER)-alpha in ER-alpha-predominant breast cancer cells, but likely acts as an antiestrogen in cells with ER-beta alone, suggesting therapeutic potential for premenopausal women with ER-alpha-negative/ER-beta-positive tumors (54). However, in an in vitro breast model, genistein also induced estrogen-dependent MCF-7 tumor cell growth and increased breast cancer-associated aromatase expression and activity, suggesting that soy-based supplements may affect the efficacy of aromatase inhibitors used in breast cancer treatment (55). Genistein is also known to negate the inhibitory effect of tamoxifen on MCF-7 tumor growth and increase expression of estrogen-responsive genes (38). Alternatively, soy isoflavones may reduce breast cancer risk by decreasing endogenous ovarian steroid levels (56). Studies suggest that some benefits ascribed to dietary isoflavones may depend on early life exposure, thereby impacting gene expression at an epigenetic level. (47) (48) (49)
In prostate cancer, soy protein extracts appear to influence the progression of established tumors rather than inhibit etiologic factors. Furthermore, soy protein consumption reduces androgen receptor expression in prostate tumors (57). Other proposed prevention mechanisms include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis (22). Growth inhibition appears to be independent of genistein’s estrogenic effects. In human prostate cancer cell lines, both genistein and daidzein affect microRNA regulation (58) and induce decreased methylation of gene promoters including BRCA1(59). In tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant prostate cancer cells, soy isoflavones enhance TRAIL-mediated apoptosis by engaging apoptotic pathways and regulating NF-κB activity (60) (61). However, in a patient-derived prostate cancer xenograft model, increased proliferation and metastasis in genistein-treated groups were linked to enhanced activities of tyrosine kinases, the epidermal growth factor receptor, and its downstream Src (40). Both genistein and daidzein also act as radiosensitizers for prostate cancer in vitro and in vivo, but pure genistein increased lymph node metastasis, whereas the combination of genistein, daidzein, and glycitein did not. Daidzein may protect against genistein-induced metastasis, and its ability to inhibit cell growth and potentiate radiation appears to be androgen-receptor-independent (62). In addition, soy isoflavones radiosensitized human A549 NSCLC cells, and decreased hemorrhages, inflammation, and fibrosis caused by radiation suggesting protection of normal lung tissue (63). The combination of genistein, daidzein, and glycitein also mediated growth-suppressive effects via ER-beta in DLD-1 human colon adenocarcinoma cells (64). 7,3’,4’-trihydroxyisoflavone (THIF), a daidzein metabolite, targets Cot and MKK4 to inhibit UVB-induced skin cancer (65) and cyclin-dependent kinases and phosphatidylinositol 3-kinase to inhibit EGF-induced proliferation and transformation in JB6 P+ mouse epidermal cells (66).
The intestinally derived isoflavone metabolite R-equol, but not S-equol, was also found to be potently chemopreventive (67). However, neonatal and prepubertal exposure to equol showed no long-term chemoprevention against DMBA-induced mammary tumors even though an equol-exposure ‘imprinting’ effect resulted in a decrease in immature terminal end structures and an increase in mature lobules (68).
The soy peptide lunasin exhibits chemopreventive properties via gene expression upregulation (69) and cell adhesion (70), apoptosis (71), and anti-inflammatory activity (72).