title: Estradiol enhances CIP2A expression by the activation of p70 S6 kinase.
abstract: Cancerous inhibitor of PP2A (CIP2A) stimulates the proliferation of various cancer cells, and 17β-estradiol (E₂) enhances the proliferation of breast cancer cells. E₂ activates epidermal growth factor receptor (EGFR), stimulating the MEK1/2 and PI3K pathways, and CIP2A expression is increased by the MEK1/2-induced transcription factor ETS1. It is possible for E₂ to increase CIP2A expression. This study examined whether E₂ could increase CIP2A expression and whether CIP2A is highly expressed in estrogen receptor (ER)-positive breast cancer tissues. E₂ increased CIP2A expression at the translational level in a c-MYC-independent manner in MCF-7 cells. E₂-enhanced proliferation was impaired without CIP2A expression. E₂-stimulated EGFR activated the MAPK and PI3K pathways, which converged to activate p70 S6 kinase (S6K). Phosphorylation at all the three phosphorylation sites (S424/T421, T229, and T389) on S6K was required for the phosphorylation of eukaryotic initiation factor 4B (eIF4B), which was responsible for the increase in CIP2A translation. Furthermore, CIP2A expression was higher in ER-positive tissues than in ER-negative tissues. This is the first study, to our knowledge, to demonstrate that CIP2A is a key factor in E₂-enhanced proliferation and that estrogen regulates CIP2A expression by non-genomic action through EGFR.
authors.affiliation: Department of Life Science, Research Center for Women's Disease, Sookmyung Women's University, Seoul 140-742, Republic of Korea Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Yeon A
authors.initials: YA
authors.lastname: Choi
authors.forename: Ja Seung
authors.initials: JS
authors.lastname: Koo
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Park
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Park
authors.forename: Ae Lee
authors.initials: AL
authors.lastname: Jeong
authors.forename: Ki-Sook
authors.initials: KS
authors.lastname: Oh
authors.forename: Young
authors.initials: Y
authors.lastname: Yang
mesh_terms: D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D066246:ErbB Receptors; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C500266:CIP2A protein, human; C512478:EGFR protein, human
keywords: CIP2A; ER-positive human breast cancer cells; MAPK pathway; PI3K/AKT; breast cancer; estradiol (E2); p70 S6K