title: Inhibition of estradiol receptor/Src association and cell growth by an estradiol receptor alpha tyrosine-phosphorylated peptide.
abstract: This report offers direct evidence that association of the estradiol receptor (ER) with Src triggered by steroid agonists or growth factors controls breast and prostate cancer cell growth. This association is abolished in whole cells and in vitro by a six-amino-acid peptide that mimics the sequence around the phosphotyrosine residue in position 537 of the human ERalpha. The phosphorylated peptide, at nanomolar concentrations, is taken up by MCF-7 and LNCaP cells derived from human mammary and prostate cancers, respectively. In addition, to block the ER/Src interaction, the phosphopeptide inhibits Src/Erk pathway, cyclin D1 expression, and DNA synthesis induced by estradiol or androgen or triggered by epidermal growth factor. In contrast, no inhibition of the Src-mediated epidermal growth factor action on DNA synthesis is detectable in human mammary cancer cells that do not express ER (MDA-MB231), indicating that the peptide specifically targets the ER-associated Src. Remarkably, the peptide, in contrast with classic steroid antagonists, does not interfere in ER- or androgen receptor-dependent transcriptional activity. Nevertheless, it markedly inhibits the growth of MCF-7 cell xenografts induced in immunodepressed and estradiol-treated mice. The present report suggests that inhibition of association of steroid receptors with Src or other signaling effectors may have therapeutic applications for patients with ER-positive tumors.
authors.affiliation: Department of General Pathology, II University of Naples, Via L. De Crecchio, 7, Naples 80138, Italy.
authors.forename: Lilian
authors.initials: L
authors.lastname: Varricchio
authors.forename: Antimo
authors.initials: A
authors.lastname: Migliaccio
authors.forename: Gabriella
authors.initials: G
authors.lastname: Castoria
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Antonietta
authors.initials: A
authors.lastname: de Falco
authors.forename: Marina
authors.initials: M
authors.lastname: Di Domenico
authors.forename: Pia
authors.initials: P
authors.lastname: Giovannelli
authors.forename: William
authors.initials: W
authors.lastname: Farrar
authors.forename: Ettore
authors.initials: E
authors.lastname: Appella
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Auricchio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D009842:Oligopeptides; C525915:acetyl-leucyl-phosphotyrosyl-aspartyl-leucyl-leucyl-leucinamide; D014443:Tyrosine; D019061:src-Family Kinases