Nuclear and extranuclear-initiated estrogen receptor signaling crosstalk and endocrine resistance in breast cancer

Abstract

Estrogens regulate function of reproductive and non-reproductive tissues in healthy and diseased states including breast cancer. They mainly work through estrogen receptor alpha (ERα) and/or estrogen receptor beta (ERβ). There are various ERα targeting agents that have been used for treatment of ER (+) breast tumors. The impact of direct nuclear activity of ER is very well characterized in ER (+) breast cancers and development and progression of endocrine resistance. Recent studies also suggested important roles for extranuclear-initiated ERα pathways, which would decrease the potency and efficiency of ERα targeting agents. In this mini-review, we will discuss the role of nuclear and extra-nuclear ER signaling and how they relate to therapy resistance in breast cancer.

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…A/B domains compose the N-terminal domain, which contains the transcription activation function-1 (AF-1). The role of AF-1 is regulating transcription activation of targeted genes ligand-independently via phosphorylation [87]. The C domain, the DNA binding domain (DBD), can mediate the binding of ERs to specific DNA sequences, such as estrogen response element (ERE).…”

“…Antagonists bind to ERs in a manner similar to estrogen, however, they induce a different conformation of LBD, resulting in recruitment of co-repressors, rather than co-activators, by inhibition of AF-2 [106]. Furthermore, the agonistic activity of tamoxifen, as seen in uterus, appears to be associated with the activation of AF-1 [87,107]. Regarding ERα, the AF-1 domain is actively involved in gene expression induced by agonists whereas the AF-1 domain of ERβ acts very weakly [108,109].…”

“…Second, estrogen also modulates the expression of genes lacking ERE-like sequences, by a tethering mechanism, in which ligand-activated ER interacts with DNA indirectly via interacting with other transcription factors at their respective response elements, such as activating protein 1 (AP-1), stimulating protein-1 (Sp-1), nuclear factor-κB (NF-κB) as some examples [110,111]. Furthermore, through the non-genomic pathway, membrane-localized ER can elicit a rapid response to ligands leading to activation of signaling transduction pathway in cytoplasm, such as PI3K/MAPK signaling pathway [87,110,111]. Additionally, ERs can regulate target gene expression in a ligand-independent manner, in which ER binds DNA directly or indirectly following ER activation through phosphorylation by growth factor signaling and other protein kinases [112,113].…”

Beyond the Antioxidant Activity of Dietary Polyphenols in Cancer: the Modulation of Estrogen Receptors (ERs) Signaling

“…ERs are modular proteins that are composed of six standard domains: A/B, C, D E, and F domains. Among them, the C domain, or DNA-binding domain (DBD), induces the dimerization of the receptor and allows the binding to the estrogen response elements (ERE) on DNA, the E or ligand-binding domain (LBD) occurs in the C -terminal region of the protein, and the hinge region (D domain) also contributes to the receptor dimerization [ 69 , 70 , 71 , 72 ]. In addition, two transcriptional activation (AF) regions are present: a ligand-independent domain (AF-1) at the protein N -terminus that corresponds to the A/B region, and a ligand-dependent one (AF-2) located at the C -terminus [ 69 , 70 , 73 ].…”

“…The ER S -palmitoylation, which occurs within the E domain, is the main determinant of the ERα and ERβ membrane localization, caveolin-1 interaction, and the activation of E2 rapid signaling [ 70 , 82 , 83 ]. E2, via the membrane-localized ERs, quickly (from seconds to minutes) induces several signal transduction pathways, including but not limited to, phospholipase C (PLC)/protein kinase C (PKC), p38/MAPK, and PI3K pathways, leading to increased levels of second messengers [ 70 , 72 , 84 ]. On the other hand, the E2–ERα complex can associate with different growth factor receptors (epidermal growth factor receptor—EGFR—or insulin-like growth factor 1 receptor—IGF1-R) on specific docking sites, evidencing the cross-talk interaction between E2 and growth factor signaling [ 85 ].…”