title: Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer.
abstract: The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50-60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.
authors.affiliation: Department of Molecular and Medical Genetics and.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Janghorban
authors.affiliation: Department of Molecular and Medical Genetics and.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Farrell
authors.affiliation: Department of Molecular and Medical Genetics and.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Allen-Petersen
authors.affiliation: Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 92739;
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: Department of Molecular and Medical Genetics and.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Daniel
authors.affiliation: Oncotide Pharmaceuticals, Inc., Research Triangle Park, NC 27709; and.
authors.forename: Jessica
authors.initials: J
authors.lastname: Oddo
authors.affiliation: Department of Molecular and Medical Genetics and.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Langer
authors.affiliation: Oncotide Pharmaceuticals, Inc., Research Triangle Park, NC 27709; andDivision of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Christensen
authors.affiliation: Department of Molecular and Medical Genetics and searsr@ohsu.edu.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
mesh_terms: D001324:Autoantigens / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D056488:Histone Chaperones / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056488:Histone Chaperones; D047908:Intracellular Signaling Peptides and Proteins; C489427:MYC protein, human; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; C513473:SET protein, human; D014157:Transcription Factors; D054648:Protein Phosphatase 2
keywords: breast cancer therapy; phosphatase activator