In the USA, breast cancer accounts for approximately 30% of all cancers diagnosed and remains the second leading cause of cancer death in women. The importance of estrogen receptor alpha (ER␣) activity in breast cancer onset is evidenced by the efficacy of ER␣ antagonists for breast cancer prevention in highrisk individuals [1,2]. The Stathmin staging classification (TNM) includes ER␣ status [3], as the abundance of ER␣ determined by immunoreactivity provides independent evidence for high survival rate and lower relapse [4,5].Estrogens regulate cellular proliferation and differentiation of the normal breast. The two related nuclear receptors, ER␣ and ER, function as transcription factors (TFs) to regulate downstream target genes, co-ordinating cell-cycle progression within the mammary epithelial cell and contribute to intracrine and paracrine signaling. ERs are members of the nuclear steroid hormone receptor family, which function as ligand-dependent transcriptional regulators. The subcellular location of the ER␣ also contributes to distinct signaling pathways. Thus, in addition to the well-known nuclear function, membrane-associated ER␣ also functions through membrane tyrosine kinase receptor signaling pathways [6]. Additional types of functional ERs associated with plasma membranes, such as GPR30, are thought to regulate non-genomic signaling through second messenger Ca 2ϩ , nitric oxide and protein-lipid kinases [7]. The ER␣ encodes distinct functional domains (termed A-F) conserved with other members of the classical receptor subclass. The conserved DNA-binding domain consists of 68 amino acids with two zinc finger structures. The activation function (AF) domains, AF-1 and AF-2, of the ER␣ contribute synergistically to transcriptional induction. AF-1 function is induced by oncoproteins, growth factors, the co-activator p300, p68 RNA helicase A and several other signaling pathways [8][9][10] Abstract Histone acetylation is thought to facilitate binding of transcription factors (TFs) to specific target DNA sequences by destabilizing nucleosomes bound to the promoter region of a target gene. In addition, non-histone proteins including a subset of TFs and co-activators are acetylated by p300/CBP and P/CAF. The regulation of estrogen signaling by direct estrogen receptor alpha (ER␣) post-translational modification reveals a novel role for histone acetyltransferase in hormone signaling. ER␣ is acetylated and phosphorylated and phosphorylation occurs at multiple sites in response to kinase signaling. The finding that mutations with the ER␣ hinge domain lysine residues enhance hormone sensitivity suggests these residues may be involved in ligand-dependent transcriptional repression or transcriptional attenuation. Phosphorylation and acetylation of the ER regulates hormone signaling and is being assessed for a role in resistance to anti-estrogen therapy of ER␣-positive patients.
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