NFκB and MAPK signalling pathways mediate TNFα-induced Early Growth Response gene transcription leading to aromatase expression

The Early Growth Response genes EGR2 and EGR3 play an important role in mediating TNFα induced aromatase expression via the adipose specific promoter PI.4. The upstream signalling pathway stimulated by TNFα to initiate this is unknown. The aim of this present study was to determine the signalling pathways activated by TNFα which result in EGR2 and EGR3 transcription, and ultimately activation of PI.4. The NFκB inhibitor BAY-11-7082 dose-dependently inhibited transcription of EGR2 and EGR3 mRNA as well as total and PI.4-specific CYP19A1 mRNA. The MAPK pathway inhibitor U0126, inhibitor of MEK1/2 had the same effect, however inhibition of c-Jun and JNK1,2,3 with SP600125 did not lead to down-regulation. We provide evidence for the first time that EGR2 and EGR3 are regulated by NFκB and MAPK signalling pathways downstream of TNFα stimulation in breast adipose fibroblasts, and that this in turn is upstream of CYP19A1 transcription via PI.4.

► TNFα upregulates estrogen in the breast, via EGRs increasing aromatase expression. ► The signalling pathways mediating this are not understood. ► NFκB signalling is constitutively active in breast adipose fibroblasts. ► Inhibition of NFκB and MAPK signalling decreases EGR and aromatase expression. ► Targetting cell signalling pathways may reduce estrogen biosynthesis in breast cancer.