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Hepatoma Derived Growth Factor (HDGF) is Essential for Breast Tumorigenesis and Downregulated by Estrogen Receptor
Author(s) -
Yang Jun,
Pedram Argani,
Dulloor Pratima,
Everett Allen D
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a31-d
Subject(s) - corepressor , carcinogenesis , cancer research , estrogen receptor , biology , chromatin immunoprecipitation , estrogen receptor alpha , growth factor , repressor , breast cancer , promoter , gene expression , cancer , receptor , gene , genetics
HDGF is a nuclear protein with mitogenic activity. Growing studies shown that HDGF plays important role in tumorgenesis and is a prognosis factor for a number of different tumors. We recently discovered that HDGF functions as a transcriptional repressor, it represses gene expression by recruiting corepressor CtBP and binds to the promoters of target genes directly. Using immunohistochemistry and western blotting to examine breast tumor samples, we show that HDGF is highly expressed in breast tumors vs normal breast tissues. By siRNA knock down approach, we found that MCF‐7 cells with endogenous HDGF knocked down lost their anchorage independent growth ability, suggesting that HDGF is essential for breast tumorigenesis. Several microarray studies indicated that HDGF expression level is associated with the status of estrogen receptor, HDGF protein is significantly low in ER negative tumors comparing with ER positive tumors. In order to study whether HDGF is negatively regulated by ER, we treated MCF 10A cells with E2 or its antagonist Tamoxifen, western blotting shown that HDGF protein level decreased about 40% after 10 nM E2 treatment for 4 hours. On the other hand, 100 nM Tamoxifen treatment increase HDGF protein level by 40%. Sequence analysis found that there are two half ERE sites in the first intron of HDGF promoter. Chromatin immunoprecipitation (ChIP) using ER specific antibody found that the second half ER site can recruit ER to HDGF promoter. Taken together, our data shown that HDGF is essential for breast tumorigenesis and HDGF is downregulated by ER, suggesting a new mechanism for increasing growth of ER‐ tumors.