Transrepression of estrogen receptor and NFκB. (a) NFκB can inhibit estrogen receptor (ER) in different ways. Activation of Akt can inhibit the activity of forkhead box O3 (FOXO3A). This protein has an important role in the synthesis of ER. Consequently, blocking FOXO3A activity leads to a reduction in the transcription of ER. Another mechanism by which NFκB can inhibit ER is by stimulating enhancer of zeste homolog 2 (EZH2) activity, which in turn will inhibit ER. Finally, NFκB (RelB) can also inhibit ER transcription by upregulating Blimp1. (b) Besides the repression of ER by NFκB, ER is also able to repress NFκB. One mechanism to block nuclear translocation of NFκB is by increasing the transcription of NFκB subunit p105, which is located into the cytosol until it is partially degraded. Activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway could also lead to accumulation of NFκB in the cytosol. A second mechanism by which ER inhibits NFκB activity is by preventing binding of the transcription factor to the DNA. In addition, NFκB activity is counteracted by the increased interaction with co-repressors and a competition for co-activators with ER. E2, estradiol.