Involvement of HP1alpha protein in irreversible transcriptional inactivation by antiestrogens in breast cancer cells.
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.
Oliva
Joan
J
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.
El Messaoudi
Selma
S
Pellestor
Franck
F
Fuentes
Maryse
M
Georget
Virginie
V
Balaguer
Patrick
P
Cavaillès
Vincent
V
Vignon
Françoise
F
Badia
Eric
E
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
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