BRCA1 Represses Amphiregulin Gene Expression

Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
Cancer Research (Impact Factor: 9.28). 02/2010; 70(3):996-1005. DOI: 10.1158/0008-5472.CAN-09-2842
Source: PubMed

ABSTRACT BRCA1, the breast cancer- and ovarian cancer-specific tumor suppressor, can be a transcriptional repressor or a transcriptional activator, depending on the promoter context. To identify the genes activated or repressed by BRCA1, we have analyzed microarray results from cells depleted of BRCA1 and revealed a number of genes regulated by BRCA1 on the level of transcription. Among the genes repressed by BRCA1, we have identified amphiregulin (AREG) and early growth response-1 (EGR1). Results indicate that BRCA1 regulates AREG transcription directly through binding to the AREG promoter, however, we could not detect BRCA1 on the EGR1 promoter, suggesting that EGR1 is indirectly regulated by BRCA1. In an attempt to identify the mechanism of the AREG transcriptional repression by BRCA1, we have mapped two independent BRCA1 response elements on the AREG located at positions -202/-182 and +19/+122. BRCA1 depletion leads to induction of the AREG protein. Taken together, our data build the connection between BRCA1 loss of function and AREG upregulation-a change in gene expression often observed in breast cancer.

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Available from: Andrew Horwitz, Jun 02, 2015
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    • "In fetal kidney differentiation, the zinc-finger transcription factor Wilms tumor suppressor (WT1) has been shown to regulate amphiregulin gene expression (Lee et al., 1999), but we did not find any WT1 expression in PHD2-and HIF-2-dependent regulation of amphiregulin MR Bordoli et al MCF-7 cells (data not shown). Recently, BRCA1 has been described as transcriptional repressor of amphiregulin and loss of BRCA1 resulted in elevated amphiregulin protein levels (Lamber et al., 2010). The role of oxygen in amphiregulin regulation is incompletely understood. "
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