title: DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells.
abstract: Breast cancer is one of the most common causes of cancer-related deaths in women. The estrogen receptor (ERα) is well known for having growth promoting effects in breast cancer. Recently, we have identified DC-SCRIPT (ZNF366) as a co-suppressor of ERα and as a strong and independent prognostic marker in ESR1 (ERα gene)-positive breast cancer patients. In this study, we further investigated the molecular mechanism on how DC-SCRIPT inhibits breast cancer cell growth. DC-SCRIPT mRNA levels from 190 primary ESR1-positive breast tumors were related to global gene expression, followed by gene ontology and pathway analysis. The effect of DC-SCRIPT on breast cancer cell growth and cell cycle arrest was investigated using novel DC-SCRIPT-inducible MCF7 breast cancer cell lines. Genome-wide expression profiling of DC-SCRIPT-expressing MCF7 cells was performed to investigate the effect of DC-SCRIPT on cell cycle-related gene expression. Findings were validated by real-time PCR in a cohort of 1,132 ESR1-positive breast cancer patients. In the primary ESR1-positive breast tumors, DC-SCRIPT expression negatively correlated with several cell cycle gene ontologies and pathways. DC-SCRIPT expression strongly reduced breast cancer cell growth in vitro, breast tumor growth in vivo, and induced cell cycle arrest. In addition, in the presence of DC-SCRIPT, multiple cell cycles related genes were differentially expressed including the tumor suppressor gene CDKN2B. Moreover, in 1,132 primary ESR1-positive breast tumors, DC-SCRIPT expression also correlated with CDKN2B expression. Collectively, these data show that DC-SCRIPT acts as a novel regulator of CDKN2B and induces cell cycle arrest in ESR1-positive breast cancer cells.
authors: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands, Marleen.Ansems@radboudumc.nl.
authors: Marleen
authors: M
authors: Ansems
authors: Jonas Nørskov
authors: JN
authors: Søndergaard
authors: Anieta M
authors: AM
authors: Sieuwerts
authors: Maaike W G
authors: MW
authors: Looman
authors: Marcel
authors: M
authors: Smid
authors: Annemarie M A
authors: AM
authors: de Graaf
authors: Vanja
authors: V
authors: de Weerd
authors: Malou
authors: M
authors: Zuidscherwoude
authors: John A
authors: JA
authors: Foekens
authors: John W M
authors: JW
authors: Martens
authors: Gosse J
authors: GJ
authors: Adema
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D014408:Biomarkers, Tumor; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C515832:ZNF366 protein, human