Expression of the BRCA1-interacting protein Brip1/BACH1/FANCJ is driven by E2F and correlates with human breast cancer malignancy.
Mutations in the BRCA1-interacting DEAH helicase Brip1 confer an increased risk of breast cancer. In the present study we aimed to unravel the transcriptional control of Brip1 and to determine its expression levels in a set of 101 primary invasive breast carcinomas. Transcription of Brip1 was found to be cell growth-related and controlled by the E2F/retinoblastoma (Rb) pathway through a conserved E2F-responsive site. Repression of Brip1 expression by the cell growth-inhibiting compound 1alpha,25-dihydroxyvitamin D3 depended on this same E2F-responsive site. In spite of its role as a tumor suppressor, both quantitative reverse transcriptase-PCR analyses and immunohistochemical stainings showed significantly elevated Brip1 expression levels in grade 3 tumors as compared to grade 1 or 2 carcinomas. Furthermore, increased Brip1 transcript levels were found in tumors with an estrogen receptor-negative, progesterone receptor-negative or HER-2-positive status. In conclusion, these data show that Brip1 is a genuine target gene for the E2F/Rb pathway and that elevated expression levels of Brip1 are detected in primary invasive breast carcinomas with unfavorable characteristics.
Eelen
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Laboratorium voor Experimentele Geneeskunde en Endocrinologie (LEGENDO), Katholieke Universiteit Leuven, Leuven, Belgium.
Vanden Bempt
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I
Verlinden
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L
Drijkoningen
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M
Smeets
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A
Neven
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P
Christiaens
M R
MR
Marchal
K
K
Bouillon
R
R
Verstuyf
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A
D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics*; D050684:E2F Transcription Factors / Q000378:metabolism / Q000502:physiology*; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D020365:RNA Helicases / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases