Abstract
Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer.
Highlights
In the past few years, much progress has been made toward a better understanding of the molecular mechanisms involved in breast cancer
We found that expression of PRDM5 was down-regulated in breast cancer, which is consistent with results previously reported [18], whereas we frequently noted overexpression of PRDM14
We found that PRDM5 was down-regulated in breast tumors, which is consistent with the earlier finding that PRDM5 is methylated in breast cancers [18] and confirms that our high-throughput approach was reliable enough for valid characterization of the gene expression profile
Summary
In the past few years, much progress has been made toward a better understanding of the molecular mechanisms involved in breast cancer Among these are mechanisms by which gene expression is regulated, including the reversible modification of core histones through acetylation, phosphorylation, or methylation [1]. The methylation of lysine residues on histone tails is catalyzed by enzymes containing a conserved Su(var), Enhancer-of-zeste and Trithorax (SET) domain. Such histone methyltransferases control epigenetic inheritance through transfer of methyl groups from the methyl donor S-adenosylmethionine to basic residues on. Up-regulated expression of one of the polycomb group genes, EZH2, which encodes a protein with H3-K27 histone methyltransferase activity, is associated with a high cell proliferation rate and aggressive breast cancers [3]. The expression of SMYD3, which contains a SET domain, is up-regulated in human breast cancer [4], and the variable number of tandem repeats polymorphism in the SMYD3 gene promoter region is associated with an increased risk of breast cancer [5, 6]
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