title: Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-alpha and the transcriptional repressor PLZF.
abstract: Estrogen receptor alpha (ERalpha) is a ligand-inducible transcription factor that acts to regulate gene expression by binding to palindromic DNA sequence, known as the estrogen response element, in promoters of estrogen-regulated genes. In breast cancer ERalpha plays a central role, where estrogen-regulated gene expression leads to tumor initiation, growth and survival. As an approach to silencing estrogen-regulated genes, we have studied the activities of a fusion protein between ERalpha and the promyelocytic leukemia zinc-finger (PLZF) protein, a transcriptional repressor that acts through chromatin remodeling. To do this, we have developed lines from the estrogen-responsive MCF-7 breast cancer cell line in which the expression of the fusion protein PLZF-ERalpha is conditionally regulated by tetracycline and shows that these feature long-term silencing of the expression of several well-characterized estrogen-regulated genes, namely pS2, cathepsin-D and the progesterone receptor. However, the estrogen-regulated growth of these cells is not inhibited unless PLZF-ERalpha expression is induced, an observation that we have confirmed both in vitro and in vivo. Taken together, these results show that PLZF-ERalpha is a potent repressor of estrogen-regulated gene expression and could be useful in distinguishing estrogen-regulated genes required for the growth of breast cancer cells.
authors.affiliation: Department of Cancer Medicine, Imperial College London, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Buluwela
authors.forename: J
authors.initials: J
authors.lastname: Pike
authors.forename: D
authors.initials: D
authors.lastname: Mazhar
authors.forename: T
authors.initials: T
authors.lastname: Kamalati
authors.forename: S M
authors.initials: SM
authors.lastname: Hart
authors.forename: R
authors.initials: R
authors.lastname: Al-Jehani
authors.forename: H
authors.initials: H
authors.lastname: Yahaya
authors.forename: N
authors.initials: N
authors.lastname: Patel
authors.forename: N
authors.initials: N
authors.lastname: Sarwar
authors.forename: N
authors.initials: N
authors.lastname: Sarwarl
authors.forename: D A
authors.initials: DA
authors.lastname: Heathcote
authors.forename: O
authors.initials: O
authors.lastname: Schwickerath
authors.forename: F
authors.initials: F
authors.lastname: Phoenix
authors.forename: R
authors.initials: R
authors.lastname: Hill
authors.forename: E
authors.initials: E
authors.lastname: Aboagye
authors.forename: S
authors.initials: S
authors.lastname: Shousha
authors.forename: J
authors.initials: J
authors.lastname: Waxman
authors.forename: N R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: A
authors.initials: A
authors.lastname: Zelent
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.forename: S
authors.initials: S
authors.lastname: Ali
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection / Q000379:methods; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C513267:Zbtb16 protein, mouse; C092037:ZBTB16 protein, human; D008156:Luciferases; D001616:beta-Galactosidase