Understanding the Phytoestrogen Genistein Actions on Breast Cancer:Insights on Estrogen Receptor Equivalence, Pleiotropic Essence andEmerging Paradigms in Bioavailability Modulation

Abstract: Prevalent as a major phenolic ingredient of soy and soy products, genistein is recognized as an eminent phytoestrogen owing to its interacting ability with estrogen receptors (ERs). The met-abolic conversion of plant-derived genistin to genistein by gut microbes and intestinal enzymes en-hances its absorption at intestinal pH of ~7.5-7.8. Genistein interferes in breast cancer (BC) devel-opment via pleiotropic actions on cell proliferation, survival, angiogenesis, and apoptosis. Though multiple investigations have demonstrated genistein intake-driven reduced BC risk, similar efficacy has not been replicated in clinical trials. Furthermore, multiple studies have structurally and func-tionally equated genistein extents with 17-β-estradiol (E2), the most available physiological estro-gen in females, culminating in aggravated BC growth. Of note, both genistein and E2 function via interacting with ERs (ERα and ERβ). However, although E2 shows almost equal affinity towards both ERα and ERβ, genistein shows more affinity towards ERβ than ERα. Our cautious literature survey revealed typical intake mode, ER expression pattern and the ratio of ERα and ERβ, transac-tivators/regulators of ERα and ERβ expression and activities, patient age, and menopausal status as decisive factors affecting genistein BC activities. Of further interest are the mechanisms by which genistein inhibits triple-negative breast cancers (TNBCs), which lack ERs, progesterone receptors (PRs), and human epidermal growth factor receptors (HER2). Herein, we attempt to understand the dosage-specific genistein actions in BC cells and patients with an insight into its better response via derivative development, nanocarrier-assisted, and combinatorial delivery with chemotherapeutic drugs.