title: Regulation of human Cripto-1 expression by nuclear receptors and DNA promoter methylation in human embryonal and breast cancer cells.
abstract: Human Cripto-1 (CR-1) plays an important role in regulating embryonic development while also regulating various stages of tumor progression. However, mechanisms that regulate CR-1 expression during embryogenesis and tumorigenesis are still not well defined. In the present study, we investigated the effects of two nuclear receptors, liver receptor homolog (LRH)-1 and germ cell nuclear factor receptor (GCNF) and epigenetic modifications on CR-1 gene expression in NTERA-2 human embryonal carcinoma cells and in breast cancer cells. CR-1 expression in NTERA-2 cells was positively regulated by LRH-1 through direct binding to a DR0 element within the CR-1 promoter, while GCNF strongly suppressed CR-1 expression in these cells. In addition, the CR-1 promoter was unmethylated in NTERA-2 cells, while T47D, ZR75-1, and MCF7 breast cancer cells showed high levels of CR-1 promoter methylation and low CR-1 mRNA and protein expression. Treatment of breast cancer cells with a demethylating agent and histone deacetylase inhibitors reduced methylation of the CR-1 promoter and reactivated CR-1 mRNA and protein expression in these cells, promoting migration and invasion of breast cancer cells. Analysis of a breast cancer tissue array revealed that CR-1 was highly expressed in the majority of human breast tumors, suggesting that CR-1 expression in breast cancer cell lines might not be representative of in vivo expression. Collectively, these findings offer some insight into the transcriptional regulation of CR-1 gene expression and its critical role in the pathogenesis of human cancer.
authors.affiliation: Laboratory of Cancer Prevention, Frederick National Laboratory for Cancer Research, Frederick, MD, USA. biancoc@mail.nih.gov
authors.forename: Caterina
authors.initials: C
authors.lastname: Bianco
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Castro
authors.forename: Christina
authors.initials: C
authors.lastname: Baraty
authors.forename: Kelly
authors.initials: K
authors.lastname: Rollman
authors.forename: Natalie
authors.initials: N
authors.lastname: Held
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rangel
authors.forename: Hideaki
authors.initials: H
authors.lastname: Karasawa
authors.forename: Monica
authors.initials: M
authors.lastname: Gonzales
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
authors.forename: David S
authors.initials: DS
authors.lastname: Salomon
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018236:Carcinoma, Embryonal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D054278:Embryonal Carcinoma Stem Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D046888:Tissue Array Analysis; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D058851:GPI-Linked Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; C082631:NR5A2 protein, human; C539950:NR6A1 protein, human; D009363:Neoplasm Proteins; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C070636:TDGF1 protein, human; C012589:trichostatin A; D014212:Tretinoin; D014635:Valproic Acid; D000077209:Decitabine; D008156:Luciferases; D015254:DNA Modification Methylases; D001374:Azacitidine