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摘要
Introduction: Several lines of evidence point to an important role for BPI, an isoform of DLX4 homeobox gene, in breast carcinogenesis and progression. BRCAI is a well-known player in the etiology of breast cancer. While familial breast cancer is often marked by BRCAI mutation and subsequent loss of heterozygosity, sporadic breast cancers exhibit reduced expression of wild type BRCAI, and loss of BRCAI expression may result in tumor development and progression. Methods: The Cister algorithm and Genomatix program were used to identify potential BPI binding sites in BRCAI gene. Real-time PCR, Western blot and immunohistochemistry analysis were performed to verify the expression of BRCAI and BPI in cell lines and breast cancer tissues. Double-stranded siRNA transfection was carried out for silencing BPI expression. ChIP and EMSA were used to confirm that BPI specifically binds to BRCAI. Results: A putative BPI binding site was identified in the first intron of BRCAI, which was confirmed by chromatin immunoprecipiation and electrophoresis mobility shift assay. BPI and BRCAI expression were inversely correlated in breast cancer cell lines and tissues, suggesting that BPI may suppress BRCAI transcription through consensus sequence binding. Conclusions: BPI homeoprotein represses BRCAI expression through direct binding to its first intron, which is consistent with a previous study which identified a novel transcriptional repressor element located more than 500 base pairs into the first intron of BRCAI, suggesting that the first intron plays an important role in the negative regulation of BRCAI. Although further functional studies are necessary to confirm its repress or activity towards BRCAI, the elucidation of the role of BPI in breast tumorigenesis holds great promise in establishing BPI as a novel target for drug therapy.
- 出版日期2010
- 单位NIH
