title: Involvement of HP1alpha protein in irreversible transcriptional inactivation by antiestrogens in breast cancer cells.
abstract: Resistance to 4-hydroxy-tamoxifen (OHT), which appears in breast cancer cells after long-term antiestrogen treatment, may involve irreversible changes of gene expression. We previously developed a MCF-7 derived cell line (MVLN), in which OHT rapidly and irreversibly inactivates the expression of an estrogen-regulated luciferase transgene (Vit-tk-luciferase). In chromatin immunoprecipitation experiments, heterochromatin protein 1 (HP1alpha) was found to be associated with the Vit-tk-luciferase transgene, only when it was inactivated by OHT treatment. Chimeras composed of either HP1alpha or the Krupple-associated box (KRAB) module of KOX-1 protein (known to repress gene expression by recruitment of HP1 proteins), fused to the estrogen receptor (ER)-DNA binding domain (DBD) and the androgen receptor (AR)-ligand binding domain (LBD) were generated and appeared as potent transcriptional repressors. In stably transfected MVLN cells, irreversible inactivation of the luciferase transgene expression obtained with HP1alpha-ER(DBD)-AR(LBD) was partial, whereas inactivation obtained with KRAB-ER(DBD)-AR(LBD) was comparable to that obtained with OHT, although with a slower kinetics. Altogether, these data suggest that HP1alpha is involved in the silencing effects associated with long-term OHT treatments.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U540, Endocrinologie Moléculaire et Cellulaire des Cancers and Université de Montpellier I, 60 rue de Navacelles, 34090 Montpellier, France.
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Selma
authors.initials: S
authors.lastname: El Messaoudi
authors.forename: Franck
authors.initials: F
authors.lastname: Pellestor
authors.forename: Maryse
authors.initials: M
authors.lastname: Fuentes
authors.forename: Virginie
authors.initials: V
authors.lastname: Georget
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Vincent
authors.initials: V
authors.lastname: Cavaillès
authors.forename: Françoise
authors.initials: F
authors.lastname: Vignon
authors.forename: Eric
authors.initials: E
authors.lastname: Badia
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004965:Estrogen Antagonists / Q000494:pharmacology*; D020868:Gene Silencing; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D019076:Transgenes; D014407:Tumor Cells, Cultured
chemical_list: C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D051741:Kruppel-Like Transcription Factors; D020033:Protein Isoforms; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C109484:ZNF10 protein, human; D013629:Tamoxifen; D000090266:Chromobox Protein Homolog 5; C016601:afimoxifene; D008156:Luciferases