Abstract. 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 immunohisto-
chemical 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 predo-
minantly 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 relation-
ship 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 demon-
strated 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.
The programmed cell death 4 gene (PDCD4) was originally
isolated from a human glioma library by screening it with an
antibody against a nuclear antigen in proliferating cells (1).
PDCD4 (H731L) is homologous to the mouse Pdcd4 gene
(also known as MA-3/TIS/A7-1) (2) and it codes for a protein
of 469 amino acids with a predicted size of 62 kDa (3,4). The
two human PDCD4 homologs, H731L and H731, are respec-
tively, 96 and 93% identical to the mouse Pdcd4 gene (5).
H731L and H731 are alternative transcripts of the same gene
with H731 lacking 11 amino acids present in the N-terminal
region of the mouse Pdcd4 and H731L (5). The human PDCD4
gene was localized to chromosome 10q24 (6) but its function
is not well defined. The deduced amino acid sequence of
PDCD4 suggests that the protein contains two N-terminal
basic domains, which may function as nuclear localization
signals and two nuclear export sequences, suggesting that
PDCD4 is capable of shuttling back to the cytoplasm under
certain conditions (2,7). Pdcd4 is now known to prevent eIF4A
from binding to eIF4G, resulting in the inhibition of cap-
dependent translation (5). PDCD4 has an intrinsic RNA-
binding activity (7) and it was postulated that it may also be
involved in RNA-processing events such as splicing and
nucleo-cytoplasmic transport. Expression of the mouse Pdcd4
gene was shown to be associated with apoptosis in several
systems (8,9). However, its role in apoptosis is yet to be
Very little is known about the upstream regulators and
downstream targets of PDCD4 in normal cells. Yang et al,
reported that Pdcd4 inhibited the activation of AP-1-dependent
transcriptional activity in a dose-dependent manner in colon
cancer cell lines (10). The serine/threonine kinase Akt is now
reported to be an upstream modulator of the Pdcd4 activity.
Akt (protein kinase B) was observed to specifically phos-
ONCOLOGY REPORTS 18: 1387-1393, 2007
Alterations in the expression of PDCD4 in
ductal carcinoma of the breast
YONG HANNAH WEN1, XIUQUAN SHI2, LUIS CHIRIBOGA1,
SACHIKO MATSAHASHI3, HERMAN YEE1and OLUBUNMI AFONJA2
1Departments of Pathology and 2Pediatrics, New York University School of Medicine, 550 First Avenue, New York,
NY 10016, USA; 3Department of Internal Medicine, Saga Medical School, Saga University, Saga 849-8501, Japan
Received April 20, 2007; Accepted August 16, 2007
Correspondence to: Dr Olubunmi Afonja, Department of
Pediatrics, New York University School of Medicine, 550 First
Avenue, New York, NY 10016, USA
Key words: programmed cell death 4, estrogen receptor, HER2/neu,
apoptosis, methylation, differentiation
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