Alterations in the expression of PDCD4 in ductal carcinoma of the breast

Department of Internal Medicine, Saga University, Сага Япония, Saga Prefecture, Japan
Oncology Reports (Impact Factor: 2.3). 01/2008; 18(6):1387-93. DOI: 10.3892/or.18.6.1387
Source: PubMed


Programmed cell death 4 gene (PDCD4), an in vivo repressor of transformation, was originally isolated from a human glioma library by screening it with an antibody against a nuclear antigen in proliferating cells. PDCD4 functions as a transformation repressor by inhibiting the activity of the RNA helicase, eIF4A. We previously showed that retinoids, anti-estrogens and HER2/neu antagonist induce PDCD4 expression in human breast cancer cell lines. Very little is known about the expression of PDCD4 in human breast cancer tissues or the significance of the PDCD4 expression in breast cancer. To gain insight into the pattern of the PDCD4 expression in breast tissues, we performed an immunohistochemical analysis of the PDCD4 expression in 80 archived, normal and ductal breast carcinoma tissues (invasive and carcinoma in situ) (DCIS) and correlated PDCD4 expression with expression of known prognostic markers in breast cancer (ER, PR and HER2/neu). To assess the role of methylation on PDCD4 expression in breast cancer cells, breast cancer cell lines were treated with the demethylating agent 5-deoxy-azacytidine and analyzed for PDCD4 expression. We observed primarily nuclear localization of PDCD4 in ductal carcinoma in situ compared to normal breast tissues where the PDCD4 expression was predominantly cytoplasmic. This was seen more frequently in DCIS cases that were ER positive and HER2/neu negative samples. PDCD4 expression was markedly decreased in the invasive ductal carcinoma. We did not observe any significant relationship between PDCD4 expression and the expression of RAR or PR. In T-47D, MDA-MB-435 and MDA-MB-231 cells, treatment with 5-deoxy-azacytidine did not result in an increased expression of PDCD4. The present study demonstrated altered cellular localization of PDCD4 when comparing normal breast to neoplastic breast tissues. In addition, there was a decreased expression of PDCD4 in breast cancer when compared with normal breast tissue. A loss of the PDCD4 expression in breast cancer cell lines does not appear to result from hypermethylation of the PDCD4 promoter.

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    • "In addition, PDCD4 was reported to be an inhibitor of neoplastic transformation and metastasis (48, 49). In breast cancer tissue, PDCD4 is seen in both normal and malignant epithelial cells and localizes to the nuclei and/or the cytoplasm (50). It remains to be established if miR-21 is involved in the regulation of all of these pivotal functions of PDCD4. "
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    • "Further investigation regarding the discriminative power of PDCD4 staining results in a prospective study is mandatory. PDCD4 seems to play an important role in various human malignancies: Loss of expression was reported in several types of human cancer cell lines [11], lung cancer [12], colorectal carcinoma [8], hepatocellular carcinoma [13], breast cancer [14], tongue cancer [15] and glioma [16]. In colon carcinoma cell lines, loss of PDCD4 promoted invasion [17]. "
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    • "anisms , such as DNA methylation , might also contribute to pdcd4 regulation . The knock - down of DNA methyltransferase 1 in a hepatocellular carcinoma cell line and , therefore , demethylation of DNA induced pdcd4 expression ( Fan et al . , 2007 ) , even if a demethylating agent resulted in no change in Pdcd4 levels in breast cancer cell lines ( Wen et al . , 2007 ) . In addition , pdcd4 5 - CpG island methylation was associated with reduced Pdcd4 mRNA levels in human glioma cell lines and tissue , and restoration of pdcd4 was observed after blocking methylation in glioma cells ( Gao et al . , 2008 ) . An overview of the known regulatory mechanisms for Pdcd4 levels is shown in Figure 2 . In concl"
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