MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells
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The peroxisome proliferator-activated receptor gamma 1 (PPARγ1) is a nuclear receptor that plays a pivotal role in breast cancer and is highly over-expressed relative to normal epithelia. We have previously reported that the expression of PPARγ1 is mediated by at least six distinct promoters and expression in breast cancer is driven by a tumor-specific promoter (pA1). Deletional analysis of this promoter fragment revealed that the GC-rich, 263 bp sequence proximal to the start of exon A1, is sufficient to drive expression in breast cancer cells but not in normal, human mammary epithelial cells (HMEC). By combining the disparate technologies of microarray and computer-based transcription factor binding site analyses on this promoter sequence the myc-associated zinc finger protein (MAZ) was identified as a candidate transcription factor mediating tumor-specific expression. Western blot analysis and chromatin immunoprecipitation assays verify that MAZ is overexpressed in MCF-7 cells and is capable of binding to the 263 bp promoter fragment, respectively. Furthermore, the over-expression of MAZ in HMEC is sufficient to drive the expression of PPARγ1 and does so by recruiting the tumor-specific promoter. This results in an increase in the amount of PPARγ1 capable of binding to its DNA response element. These findings help to define the molecular mechanism driving the high expression of PPARγ1 in breast cancer and raise new questions regarding the role of MAZ in cancer progression.
KeywordsPPARγ1 peroxisome proliferator activated receptor gamma Breast cancer HMEC MAZ Myc-associated Zinc finger protein MCF-1
We would like to thank Dr Victoria Seewaldt from Duke University for her generosity in sharing unpublished data. We also appreciate the assistance with experimental design and statistical analysis from Drs Kuey-Chu Chen, Arnold Stromberg and Eric Blalock from the University of Kentucky. This work was supported by grants CA95609-01 to MWK, grants 5-K12-DA-14040-05 and NCRR-P20-RR15592 to MWK and MEW, grant HL073693 to MEW, CA117235-02 from the NIH to DRT, and grant W81XWH-04-1-0532 to CDA.
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