Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature

Saori Furuta, Ju Ming Wang, Shuanzeng Wei, Yung Ming Jeng, Xianzhi Jiang, Bingnan Gu, Phang Lang Chen, Eva Y.H.P. Lee, Wen Hwa Lee

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

BRCA1 exerts transcriptional repression through interaction with CtIP in the C-terminal BRCT domain and ZBRK1 in the central domain. A dozen genes, including angiopoietin-1 (ANG1), a secreted angiogenic factor, are corepressed by BRCA1 and CtIP based on microarray analysis of mammary epithelial cells in 3D culture. BRCA1, CtIP, and ZBRK1 form a complex that coordinately represses ANG1 expression via a ZBRK1 recognition site in the ANG1 promoter. Impairment of this complex upregulates ANG1, which stabilizes endothelial cells that form a capillary-like network structure. Consistently, Brca1-deficient mouse mammary tumors exhibit accelerated growth, pronounced vascularization, and overexpressed ANG1. These results suggest that, besides its role in maintaining genomic stability, BRCA1 directly regulates the expression of angiogenic factors to modulate the tumor microenvironment.

Original languageEnglish
Pages (from-to)13-24
Number of pages12
JournalCancer Cell
Volume10
Issue number1
DOIs
Publication statusPublished - 2006 Jul

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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