Immunohistochemical profiles of claudin-3 in
primary and metastatic prostatic adenocarcinoma
Tanner L Bartholow1†, Uma R Chandran2, Michael J Becich2, Anil V Parwani3*†
Background: Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One
member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic
cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH),
prostatic intraepithelial neoplasia (PIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic
adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets).
Methods: Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities
subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for
multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107
cases of PCa, and 55 cases of Mets were analyzed in the microarrays.
Results: PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than
BPH (p < 0.05 in both cases) and NAC (p < 0.05 in both cases). PIN had a lower, but non-significant, staining score
than PCa and Mets, but a statistically higher score than both BPH and NAC (p < 0.05 for both cases). No significant
differences were observed between PCa, Mets, and PIN.
Conclusions: To our knowledge, this represents one of the first studies comparing the immunohistochemical
profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence
that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not
provide evidence that claudin-3 can be used to predict risk of metastasis.
During 2010 alone, 32,050 deaths attributable to prostate
cancer are expected to occur in the United States, mak-
ing it the second leading cause of cancer death in males
. Despite this, studies conducted before the era of
prostate specific antigen (PSA) screening have shown
that latent prostate cancer was often diagnosed only after
autopsy in older males [2-4]. One autopsy study of males
over the age of 50, also conducted before PSA screening
was implemented, indicated that the overall age-adjusted
prevalence of latent prostate carcinoma was as high as
34.6% for whites and 36.9% for blacks in the United
States , providing evidence that not all cases of pros-
tate cancer have the same clinical aggressiveness. Based
upon cases of prostate cancer diagnosed by PSA,
researchers have estimated that clinically insignificant
prostate cancer is now actually overdiagnosed at a rate of
29% for whites and 44% for blacks, the PSA screen result-
ing in the detection of cancers that otherwise would only
have been detected during autopsy in up to 15% and 37%
of tumors in whites and blacks, respectively .
There is limited information in the literature on predic-
tive biomarkers to discern which cases of prostate cancer
are likely to remain latent, versus those that are likely to
metastasize and warrant more aggressive management
. Understanding the protein expression patterns asso-
ciated with prostate adenocarcinoma may provide a new
toolset to aid in the diagnosis of prostate cancer, provide
prognostic information about the risk of metastasis, and
indicate unique treatment targets.
Cellular tight junctions have been shown to play roles
in maintaining cell polarity, regulating ion flow, and
signalling [8-13]. Given that the disruption of tight
* Correspondence: firstname.lastname@example.org
† Contributed equally
3Department of Pathology, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA
Full list of author information is available at the end of the article
Bartholow et al. Diagnostic Pathology 2011, 6:12
© 2011 Bartholow et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
junctions is believed to be one facet of tumorigenesis
, claudins, one of the transmembrane protein families
hypothesized to be the backbone of tight junctions ,
have become a target of focus in the recent cancer
One specific member of this family, claudin-3, has been
shown to be overexpressed in multiple forms of cancer,
having been most thoroughly studied in ovarian cancer,
where it has been shown to be up regulated more than
80-fold in comparison to normal ovarian cells . In
ovarian serous adenocarcinoma, its increased expression
has also been associated with shorter survival times .
Additional studies have shown that it is also up regulated
in breast, pancreatic, bladder, thyroid, fallopian tube,
ovary, stomach, colon, and uterine cancer . Moreover,
it has been observed in 18% of mesotheliomas and 90% of
cases of metastatic lung adenocarcinoma . A signifi-
cant inverse relationship between claudin-3 expression
and overall survival in renal clear cell carcinoma has
been documented .
In prostate cancer specifically, claudin-3 has been
shown to correlate with advanced tumor stage and
recurrence, although the immunohistochemical expres-
sion profiles varied in an examination of 141 cases of
prostate cancer, where matched adjacent normal epithe-
lium was compared to prostatic adenocarcinoma (PCa).
In 31% of cases, the expression was actually lower than
in the matched PCa .
Here, we compare the immunohistochemical profiles in
a series of 53 cases of normal tissue adjacent to prostatic
adenocarcinoma (NAC), 17 cases of benign prostatic
hyperplasia (BPH), 35 cases of prostatic intraepithelial
neoplasia (PIN), 107 cases of PCa, and 55 cases of meta-
static prostatic adenocarcinoma (Mets) in order to obtain
a more complete understanding of the immunostaining
profile of claudin-3 in primary and metastatic prostate
cancer and to further examine its potential as a biomar-
ker for prostate cancer and/or prostate cancer metastasis.
Preparation of Tissue Microarray Blocks
Two sets of tissue microarray (TMA) blocks were con-
structed using specimens located in the Health Sciences
Tissue Bank at the University of Pittsburgh Medical
Center. Cores were taken from the appropriate case spe-
cific paraffin-embedded tissue blocks and assembled into
TMAs according to a previously described protocol .
The final TMAs consisted of 53 cases of NAC, 17 cases
of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases
of Mets. Each case was represented at least in triplicate,
however, in some cases, due to processing, only two
cores for each case were represented. In these instances,
the cases were still included in the analysis.
Each TMA block was deparaffinized and then rehydrated
with incremental ethanol concentrations. Decloaker was
then used for heat induced epitope retrieval, followed by a
5 minute TBS buffer rinse. A Dako Autostainer was then
used to stain the TMAs with anti-claudin-3 (working dilu-
tion 1:150), a rabbit polyclonal antibody (Catalogue #
RB-9251-PO) from Thermo Scientific (Waltham, MA,
USA). Immunolabeling was conducted using Rabbit Envi-
sion + HRP Polymer (Catalogue # K4003) from Dako
(Carpinteria, CA). Slides were counterstained with hema-
toxylin before being coverslipped.
Scoring of Slides
Slides were scored on a scale of staining intensity, with
0 representing no staining, 1 representing weak staining,
2 representing moderate staining, and 3 representing
strong staining. Each staining value was multiplied by
the percentage of the core that stained for that intensity,
expressed as a whole number. For cores where more
than one intensity was represented, the sum of the
staining values was calculated. An average value was
obtained for each case, and subsequently, each tissue
type. This scoring procedure was modified from a scor-
ing protocol previously used by Parwani, et al .
Means by Gleason score and tumor stage, where avail-
able, were also obtained. All means were reported with
standard error. A one-way ANOVA with subsequent
Tukey tests for multiple comparisons or nonparametric
Kruskal-Wallis test with post-hoc Dunn’s tests (a = 0.05
in both cases) were used to compare the tissue types,
PCa carcinoma stages, and PCa Gleason scores.
Photomicrographs of tissue cores were taken using an
Olympus BX51 microscope using Spot Advanced V4.6
(Diagnostic Instruments, Inc.) software. All images were
taken at 20x.
This study received exempt approval (PRO08040368)
from the University of Pittsburgh Institutional Review
The mean staining scores for NAC, BPH, PIN, PCa, and
Mets were 71.42 ± 8.78, 60.23 ± 9.42, 108.76 ± 7.67,
117.03 ± 5.38, and 116 ± 7.66 (Figure 1).
A Kruskal-Wallis test (p = < 0.001), with subsequent
Dunn’s tests showed significant differences between
NAC and PCa, BPH and PCa, NAC and Mets, BPH and
Mets, NAC and PIN, and BPH and PIN (p < 0.05 in all
cases). No significant differences were seen between PCa
and Mets or PCa and PIN (p > 0.05 in both cases).
Twelve of 53 cases (23%) of NAC, 2 of 17 cases (12%)
of BPH, 20 of 35 cases (57%) of PIN, 64 of 107 cases
Bartholow et al. Diagnostic Pathology 2011, 6:12
Page 2 of 6
(60%) of PCa, and 33 of 55 cases (60%) of Mets had
staining scores higher than 100.
When classified by Gleason score, the average staining
score was 113.63 ± 12.08 (n = 17) for those with a score
of 6 or less, 116.81 ± 8.42 (n = 51) for those with a
score of 7, and 118.80 ± 8.53 (n = 39) for those with a
score of 8 or more (Figure 2). A resultant one-way
ANOVA showed no significant differences (p = 0.9504).
Twelve of 17 cases (71%) with a Gleason score of 6 or
less, 29 of 51 cases (57%) with a Gleason score of 7, and
24 of 39 cases (62%) with a Gleason score of 8 or higher
had staining scores higher than 100.
When classified by tumor stage, the mean scores were
stage 2, 134.34 ± 10.25 (n = 39), stage 3, 98.25 ± 6.91 (n =
38), and stage 4, 113.95 ± 8.88 (n = 29) (Figure 3). A resul-
tant one-way ANOVA (p = 0.013) with subsequent Tukey
tests for multiple comparisons showed significant differ-
ences between stage 2 and stage 3 (p = 0.010). Twenty-
eight of 39 cases (72%) of stage 2 carcinoma, 18 of 38
cases (47%) of stage 3 carcinoma, and 18 of 29 cases (62%)
of stage 4 carcinoma had staining scores higher than 100.
Representative photomicrographs of the TMA cores
are shown in Figure 4. Claudin-3 staining was a predo-
minantly membranous in positive cases, although in
some cores, depicted most prominently in the primary
and metastatic photomicrographs, additional cytoplas-
mic staining was also noted.
In the claudin-3 stained specimens, the average staining
scores were highest in PCa and Mets. PIN had a lower
absolute staining score than PCa and Mets, although the
differences were not significant. Both BPH and NAC had
significantly less staining than PCa and Mets (Figure 1).
Figure 1 Mean claudin-3 staining score by prostatic tissue type. Mean claudin-3 staining score by prostatic tissue type. Significant
differences were seen between NAC and PIN, NAC and PCa, NAC and Mets, BPH and PIN, BPH and PCa, and BPH and Mets (p < 0.05 for each).
No differences were seen between PCa, Mets, and PIN.
Mean Claudin-3 Staining Intensity by Gleason Score
6 or Less78 or More
Figure 2 Mean claudin-3 staining score by Gleason score. Mean
claudin-3 staining score by PCa Gleason score. No significant
differences were seen by this classification (P = 0.950).
Bartholow et al. Diagnostic Pathology 2011, 6:12
Page 3 of 6
These differences support the notion that claudin-3 is
upregulated in many cases of prostatic adenocarcinoma.
It does not appear that stronger expression exists in all
cases, however, as there were 42 cases of PCa and 22
cases of Mets that had staining scores below 100.
Previous studies have shown that Gleason scores of 7
or higher were more frequently associated with lower
expression of claudin-1 . Additionally, Landers,
et al., demonstrated that claudin-4 was upregulated in
primary and metastatic prostate cancer, although they
state that it tended to be expressed more in primary
tumors with a Gleason score of 6 than those with a
score of 7 or higher . In this current study, no sig-
nificant differences were seen when the cases of PCa
were compared by Gleason score (Figure 2).
Sheehan, et al., have also reported that claudin-3
expression correlates with advanced stage and tumor
recurrence in prostate cancer , which coincides with
another study of urothelial carcinoma, where claudin-3
has also been shown to correlate with advanced stage
and poor survival . In this current study, however,
the highest average staining appeared to be in stage 2
PCa, which was significantly higher than stage 3 PCa
staining, but not significantly higher than that noted in
stage 4 PCa (Figure 3). Although statistically different, it
is worth noting that these absolute staining scores are
similar, reflecting that the difference in stage staining
may not be of enough magnitude to use clinically. In a
study of gastric cancer, claudin-3 has also been shown
to be less expressed in advanced stage cases , which
may suggest that claudin family expression patterns vary
by cancer type.
As claudin-3 is a tight junction protein, it is interest-
ing to note that in addition to membranous staining,
cytoplasmic staining was also seen in select cores, most
prominently in cases of PCa and Mets (Figure 4). Ran-
gel, et al., have reported positive cytoplasmic immunos-
taining for claudin-3 in ovarian tumors and have
suggested that this mislocation may be the result of
abnormal pathway activation in cancer . This finding
may indicate that a similar occurrence takes place in
prostate cancer and may warrant further investigation.
Based on this study, it appears that claudin-3 is moder-
ately to strongly expressed in the majority of cases of pros-
tate cancer and may serve as an important biomarker for
prostate cancer diagnosis, both primary and metastatic,
however the discrimination between primary and meta-
static cases in this study is not great enough to merit its
usage as a marker to predict the risk of metastasis.
Some groups have speculated on the specific mechan-
ism whereby claudin-3 may be involved in carcinogen-
esis. D’Souza, et al., have shown that tight junction
strength decreased when claudin-3, when designed to
contain a T192D mutation mimicking a phosphorylated
state, was overexpressed in ovarian cancer cell line
OVCA433, a mechanism possibly enabling invasion .
Additionally, Agarwal, et al, have noted that ovarian
epithelial cells specifically designed to constitutively
express claudin-3 were found to have higher activity of
matrix metalloproteinase-2, which may also contribute to
invasion, although this level did not decrease following
siRNA knockdown of claudin-3, possibly indicating that
other pathways also promote its expression . This
could be one explanation for the fact that strong claudin-
3 staining is not noted in all cases of PCa.
Finally, in addition to its potential role as a predictive
biomarker for cancer, claudin-3 has also been shown to
bind clostridium perfringens enterotoxin, subsequently
leading to toxin-mediated cytolysis, prompting some to
suggest that this may indicate a future therapy in select
cases of prostate cancer [31,32]. Should such a therapy
be developed, the immunohistochemical profiles of
patients for this marker may become even more impor-
tant, as it may serve to guide therapy selection.
These results provide a basis for the characterization of
claudin-3 staining in both primary prostatic adenocarci-
noma and metastatic prostatic adenocarcinoma. In both
types of tissue, increased expression of claudin-3 was
seen in the majority of cases examined, and was seen
more frequently than in non-neoplastic tissue, indicating
that it may serve as an important biomarker for prostate
cancer. Despite this, the differences in primary and
metastatic cancers were not enough to indicate that a
claudin-3 immunostain could provide prognostic infor-
mation about the risk of metastasis. Furthermore, no
significant differences were seen when the cases of PCa
Mean Claudin-3 Staining Intensity by Carcinoma
Stage 2Stage 3 Stage 4
Figure 3 Mean claudin-3 staining score by carcinoma stage.
Mean claudin-3 staining score by PCa carcinoma stage. Significant
differences were seen between stage 2 and stage 3 (p = 0.010).
Bartholow et al. Diagnostic Pathology 2011, 6:12
Page 4 of 6
were compared by Gleason score. While stage 2 mean
staining was significantly greater than stage 3, the
numerical differences were similar in absolute. Given its
high expression in the majority of cases of prostate
cancer, and the fact that it has been implicated as a pos-
sible therapeutic target, claudin-3 warrants additional
studies to evaluate its potential as a clinically useful bio-
marker in the diagnosis of prostate cancer.
This work was supported by the Clinical and Translational Science Institute
Multidisciplinary Predoctoral Fellowship program, awarded through the
Clinical and Translational Science Institute and the Institute for Clinical
Research Educational Education at the University of Pittsburgh (grant
5TL1RR024155-02 and grant 5TL1RR024155-05) to Tanner L. Bartholow.
Additional funds were provided by the Doris Duke Charitable Foundation,
and the Departments of Pathology and Biomedical Informatics at the
University of Pittsburgh.
The authors of this paper would like to thank Marianne Notaro for assistance
with TMA preparation, Marie Acquafondata for assistance with
immunohistochemical staining, and the Clinical Scientist Training Program,
funded by the Office of the Dean at the University of Pittsburgh School of
1University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
2Department of Biomedical Informatics, University of Pittsburgh School of
Medicine, Pittsburgh, PA, USA.3Department of Pathology, University of
Pittsburgh School of Medicine, Pittsburgh, PA, USA.
TB assisted in scoring tissue microarrays under the direct supervision of an
attending pathologist, performed the statistical calculations, and drafted the
manuscript. UC assisted with statistical calculations and reviewed the
manuscript. AP conceived of the study, developed and approved the study
protocol, approved all tissue microarray scoring, and revised the manuscript.
Figure 4 Photomicrographs of TMA cores. Photomicrographs of TMA cores (20x). A) NAC, B) BPH, C) PIN, D) PCA, and E) Mets. Average
staining was higher in PCa and Mets than in NAC and BPH. The immunostain was predominantly membranous in positive cases, however
cytoplasmic staining was additionally noted in select cores as depicted most prominently here in the photomicrographs of PCa and Mets.
Bartholow et al. Diagnostic Pathology 2011, 6:12
Page 5 of 6
MB also conceived of the study, developed and approved the protocol, and
revised the manuscript. All authors have read and approved the final
The authors declare that they have no competing interests.
Received: 2 January 2011 Accepted: 21 January 2011
Published: 21 January 2011
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Cite this article as: Bartholow et al.: Immunohistochemical profiles of
claudin-3 in primary and metastatic prostatic adenocarcinoma.
Diagnostic Pathology 2011 6:12.
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