Methylation, a key step for nongenomic estrogen signaling in breast tumors.
Estrogen receptor alpha (ERalpha) is a member of a large conserved superfamily of steroid hormone nuclear receptors which regulates many physiological pathways by acting as a ligand-dependent transcription factor. Evidence is emerging that estrogens also induce rapid signaling to the downstream kinase cascades; however the mechanisms underlying this nongenomic function remain poorly understood. We have recently shown that ERalpha is methylated specifically by the arginine methyltransferase PRMT1 at arginine 260 in the DNA-binding domain of the receptor. This methylation event is required for mediating the extra-nuclear function of the receptor which would thereby interact with Src/FAK and p85 and propagate the signal to downstream transduction cascades that orchestrate cell proliferation and survival. Of particular interest, a possible role of methylated ERalpha in mammary tumorigenesis is also evident by the fact that, as demonstrated by immunohistochemical studies on a cohort of breast cancer patients, ERalpha is methylated in normal epithelial breast cells and is hypermethylated in a subset of breast cancers. Hypermethylation of ERalpha in breast cancer might cause hyperactivation of cellular kinase signaling, notably of Akt, described as a selective survival advantage for primary tumor cells even in the presence of anti-estrogens. A detailed understanding of the molecular mechanisms that control estrogen signaling in breast cancer is a crucial step in identifying new effective therapies.
Le Romancer
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M
Equipe labellisée La Ligue, U590 INSERM, Centre Léon Bérard, 28 rue Laennec, Lyon F-69008, France. corbo@lyon.fnclcc.fr
Treilleux
I
I
Bouchekioua-Bouzaghou
K
K
Sentis
S
S
Corbo
L
L
D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D008745:Methylation; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases