Fig. 2

NF-κB signaling pathways mediated by classical ER. In general, upon binding to ERα in the membrane, cytoplasm or nucleus, E2 can inhibit the activation of NF-κB by regulating TLR4, MS-KIF18A, ERK, AKT, CREB, SIRT1 and other signal transduction molecules, thereby decreases the expression of the proinflammatory cytokines TNF-α, IL-1β and IL-6. However, supraphysiologic doses of E2 (sE2) abnormally activate NF-κB in microglia, resulting in increased expression of IBA1, CD86 and the proinflammatory cytokines TNF-α, IL-1β, and IL-6 and decreased expression of the anti-inflammatory cytokines TGF-β, IL-10, and IL-4. Moreover, E2 can promote the proliferation, migration and invasion of ER⁺ breast cancer cells by activating the PI3K/AKT/NF-κB/TWIST1/CCL2 signaling pathway