Crossroads of Estrogen Receptor and NF-κB Signaling

Abstract

Cellular homeostasis in higher organisms is maintained by balancing cell growth, differentiation, and death. Two important systems that transmit extracellular signals into the machinery of the cell nucleus are the signaling pathways that activate nuclear factor kappaB (NF-kappaB) and estrogen receptor (ER). These two transcription factors induce expression of genes that control cell fates, including proliferation and cell death (apoptosis). However, ER has anti-inflammatory effects, whereas activated NF-kappaB initiates and maintains cellular inflammatory responses. Recent investigations elucidated a nonclassical and nongenomic effect of ER: inhibition of NF-kappaB activation and the inflammatory response. In breast cancer, antiestrogen therapy might cause reactivation of NF-kappaB, potentially rerouting a proliferative signal to breast cancer cells and contributing to hormone resistance. Thus, ER ligands that selectively block NF-kappaB activation could provide specific potential therapy for hormone-resistant ER-positive breast cancers.

Neuronal Estrogen Receptor-α Mediates Neuroprotection by 17β-Estradiol

“…Intracellular signaling pathways leading to neuroprotection involve PI3K, AKT, and MAP kinases (Morrison et al, 2006). In addition, ERs are known to inhibit the transcription factor nuclear factor-kB (Biswas et al, 2005), an effect that has also been reported in a model of cerebral ischemia in vivo (Wen et al, 2004). Inhibition of nuclear factor-kB in neurons is protective in stroke models Zhang et al, 2005), suggesting that pathwayselective ER ligands that inhibit nuclear factor-kB (Chadwick et al, 2005) might be an option for stroke treatment.…”

Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

“…There has been accumulating evidence that estradiol activates gene expression without direct DNA binding by ER (Biswas et al 2005). The nongenomic actions of estradiol include effects on calcium flux that occur rapidly without being mediated by transcriptional effects of nuclear ER (Nadal et al 2001, Song et al 2002, Gaben et al 2004.…”

Cross-talk between nuclear receptors and nuclear factor κB

“…Because most results suggest that inhibition of the NF-kB pathway is a valid strategy to combat breast cancer in many individuals, continued research now focuses on the development of SERMs that are not only anti-proliferative but also antiinflammatory and possibly pro-apoptotic. Many currently used SERMS do not have the capacity to efficiently block NF-kB (Biswas et al, 2005); however, raloxifene has recently been shown to remove RelA from DNA in an ERa-dependent manner in multiple myeloma cells (Olivier et al, 2006). In addition, the recently developed non-steroidal compound WAY-169916 can selectively block NF-kB signaling through binding to either ERa or ERb, but fails to induce classical ER-mediated target gene effects, suggesting that such compounds could be valuable for the treatment of ER-positive breast cancers where inhibition of NF-kB can induce apoptosis (Chadwick et al, 2005).…”

“…The advantage of NF-kB-selective ER modulators may lie in their ability to block the proliferative and pro-survival effects of enhanced NF-kB signaling, which currently is an inevitable side effect and a possible cancer-promoting event, when estrogen signaling is completely inhibited by current ER-positive breast cancer treatments with aromatase inhibitors (which block estrogen synthesis) (Biswas et al, 2005). The importance of ER-mediated inhibition of NF-kB in breast cancer is further supported by the observation that active DNA-bound NF-kB is detected in the majority of ER-negative breast tumors, whereas active NF-kB is absent in their ERpositive counterparts (Biswas et al, 2004).…”