In addition to the conventional hormone-dependent regulation of activity of Estrogen receptor alpha and beta (ESR1(nuclear) and ESR2 respectively), there is a cross-talk between signal transduction pathways and estrogen receptors [1]. Epidermal growth factor (EGF), Insulin-like growth factor-1 (IGF-1), stimulators of cAMP-dependent signaling pathway regulate transcriptional activity of the ESR1(nuclear) and ESR2 in the absence of ligand [2], [3], [4]. Regulators of ESR1 (nuclear) and ESR2 transcriptional activity activate multiple signaling pathways.

EGF and IGF-1 activate ESR1(nuclear) by binding to the corresponding receptors (Epidermal growth factor receptor (EGFR) and Insulin-like growth factor 1 receptor (IGF-1 receptor) respectively) followed by stimulation of mitogen-activated protein kinases (MAPK) cascade - signaling pathway. ESR2 is activated only by EGF signaling [5], [6]. The adaptors Src homology 2 domain-containing transforming protein 1 (Shc) and Growth factor receptor-bound protein 2 (Grb2) recruit exchange factor Son of sevenless homolog (SOS), forming a protein complex Shc / Grb2 / SOS. Activated SOS stimulates small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) by its conversion from the inactive GDP-bounding state to the active GTP-bounding state. The activated H-RAS stimulates v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))/ Mitogen activated protein kinases 1-3 (ERK1/2) cascade, which leads to higher transcriptional activity of ESR1 (nuclear) and ESR2. ERK1/2 can activate ESR1 (nuclear) and ESR2 by direct phosphorylation [5], [7], [8] or via phosphorylation of coregulatory proteins such as Nuclear receptor co-activators 1, 2 and 3 (NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3), respectively) [9], [10], [11].

EGF also activates Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1) (most probably through MAP kinases pathway), which phosphorylates and enhances transcriptional activity of ESR1 (nuclear) [8], [12].

The second pathway which stimulates exclusively ESR1 (nuclear) by EGF and IGF-1 includes activation Phosphoinositide-3-kinase (PI3K)/ V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) cascade. EGFR (directly) and IGF-1 receptor (via Insulin receptor substrate 1 (IRS-1)) activate PI3K which converts phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3). PtdIns(3,4,5)P3 associates with the inner face of the plasma membrane promoting the recruitment and activation of the AKT(PKB). Both PI3K and AKT(PKB) phosphorylate ESR1 (nuclear) [8], [13], [14], [15].

Neuregulin-1 also activates ESR1 (nuclear) in a ligand-independent manner via PI3K/ AKT(PKB) pathway. Neuregulin-1 interacts with an v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog of (ErbB2)/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ErbB3) heterodimers; activated ErbB3 recruits and activates PI3K and, consequently, AKT(PKB) and ESR1 (nuclear) phosphorylated by AKT(PKB) [16].

Stimulation of cAMP/ Protein kinase, cAMP-dependent (PKA) signaling likely proceeds via G-protein alpha-s which activates Adenylate cyclase. Activation of PKA by cAMP is the third ligand-independent signaling pathway which stimulates ESR1 (nuclear) [2], [8], [15].

During stimulation of cAMP signaling pathway, coactivator Cyclin D1 enhances transcriptional activity of ESR1 (nuclear) in a ligand-independent manner [1], [17].

Co-regulatory proteins NCOA1 (SRC1), NCOA2 (GRIP1/TIF2) and NCOA3 (pCIP/SRC3) in response to growth factors overall ligand-independent ESR activation may be due to more efficient recruitment of coactivators to the ESR1 (nuclear) and ESR2 [10], [18], [19]. Phosphorylation of ESR1 (nuclear) increases affinity of coactivators such as NCOA3 [15]. ESR1 (nuclear)-coactivator complex then recruits integrator proteins such as CREB binding protein (CBP) and E1A binding protein p300 (p300), which by DNA looping brings the receptor-containing regulatory region of the gene into proximity with the actual transcriptional start site [10], [18].

Caveolin 1, caveolae protein, 22kDa (Caveolin-1) is yet another co-activator of ESR1 (nuclear) in a ligand-independent manner, which drives ERK-independent phosphorylation and activation of AF-1 domain [20].

Ligand-independent transcriptional activation of ERS1 (nuclear) and ESR2 pathways results in transcription of Trefoil-factor protein 1 (TFF1) [14], [18], [21]. TFF1 display a great number of physiological actions [22], [23], [24]. Its role in ligand-independent ESR activation is not yet resolved. ERS1 (nuclear) and ESR2 inhibit cell migration and invasion and ESR2 inhibits cell proliferation in a ligand-independent manner [25], [26].

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