NFκB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms

• NFκB signaling down-regulates ER expression.
• NFκB and ER bind cooperatively to regulatory regions to increase transcription.
• NFκB affects ER activity through phosphorylation and ligand-independent activation.
• NFκB can potentiate ER-dependent gene repression.

Estrogen receptor (ER) and NFκB are two widely expressed, pleiotropic transcription factors that have been shown to interact and affect one another’s activity. While the ability of ER to repress NFκB activity has been extensively studied and is thought to underlie the anti-inflammatory activity of estrogens, how NFκB signaling affects ER activity is less clear. This is a particularly important question in breast cancer since activation of NFκB in ER positive tumors is associated with failure of endocrine and chemotherapies. In this review, we provide an update on the multiple mechanisms by which NFκB can influence ER activity, including down-regulation of ER expression, enhanced ER recruitment to DNA, and increased transcriptional activity of both liganded and unliganded ER. Additionally, a novel example of NFκB potentiation of ER-dependent gene repression is reviewed. Together, these mechanisms can alter response to endocrine therapies and may underlie the poor outcome for women with ER positive tumors that have active NFκB signaling.