Original Article | Iran J Pathol.

2025; 20(2): 167-172

Iranian Journal of Pathology | ISSN: 2345-3656

Evaluation of the Role of Claudin-4 Antigen Overexpression in Triple-Negative

Breast Cancer Patients: A 5-Year Survival Analysis
Maryam Soltan 1 , Azar Naimi 1* , Razieh Hafez Forghan 2, Marjan Mansourian 3
1. Department of Pathology, Reproductive Sciences and Sexual Health Research Center, Isfahan University of Medical Sciences,
Isfahan, Iran
2. School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3. School of Health, Department of Biostatistics and Epidemiology, Isfahan University of Medical Sciences, Isfahan, Iran

KEYWORDS ABSTRACT
Breast Neoplasms, Claudin-4, Biomarkers,
Prognosis, Neoplasm Metastasis
Background & Objective: Breast cancer (BC) can be categorized into 4 groups based
on molecular and pathological evidence: Luminal A, Luminal B, HER2+ tumors, and
Scan to discover online triple-negative breast cancer (TNBC). TNBC has a poorer survival rate and a higher
chance of recurrence and metastasis compared to other BC types, primarily due to its
challenging treatment course. Claudin 4 (CLDN4), a transmembrane protein in tight
junctions between cells, has been linked to poor prognosis and faster disease
progression in these malignancies.
Methods: Patients previously diagnosed with TNBC and tested for CLDN4 overexpression
were contacted for follow-up and to determine disease outcomes. The current health status,
cause, and time of death (if applicable) were recorded. Patient files were accessed to obtain
Main Subjects: information on age, tumor size and grading, lymph node involvement, metastasis, Ki67, and
Breast Pathology CLDN4 expression.
Received 02 Sep 2024; Results: Patients with high CLDN expression showed a significantly lower mortality
Accepted 28 Dec 2024; rate. However, after controlling for other covariates, the hazard ratio (HR) was 0.48
Published Online 10 Mar 2025; (95%CI= [0.13 – 1.27]) in the crude model for survival, 0.54 (95%CI = [0.2 – 1.43])
when adjusted for age at diagnosis, and 0.58 (95%CI = [0.18-1.82]) when adjusted for
10.30699/ijp.2025.2040168.3350 other covariates. CLDN4 was also not correlated with tumor metastasis (HR=0.64,
p=0.203, in the crude model; HR=0.52, p=0.409, when adjusted for other covariates).
Patients in the CLDN4 high group had a significantly higher number of tumors >2cm.
Conclusion: Although previous studies have shown that CLDN4 overexpression worsens
TNBC prognosis and increases metastasis or recurrence, the current study found no such
association.
Azar Naimi, Associated Professor, Department of Pathology, Faculty of Medicine, Isfahan University of Medical
Corresponding Information:
Sciences, Isfahan, Iran. Email: [email protected]
Copyright © 2025. This is an open-access article distributed under the terms of the Creative Commons Attribution- 4.0 International License which permits Share, copy
and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, even commercially.

Introduction
Breast cancer (BC) reigns as the most common Ki-67, and HER2 (5). As such, BC is grouped into
malignancy affecting women globally, posing a Luminal A (ER-positive (ER+), PR positive, HER2
significant public health burden (1, 2). Each year, over negative, Ki67 <14%) (6), Luminal B‐like (HER2‐
1.3 million new cases are diagnosed, tragically negative) tumors (ER+, HER2 negative, and Ki67
resulting in roughly 460,000 deaths (3). The relentless ≥14%), Luminal B‐like (HER2‐positive [HER2+])
pursuit of earlier BC detection and treatment strategies tumors (ER+, HER2+, any Ki67 level), HER2+ (non‐
remains a paramount focus. Regardless of BC subtype, luminal) tumors (HER2+ and ER and PR negative) and
early identification and appropriate intervention are finally triple‐negative (ductal) tumors are defined as
crucial for improved prognosis and reduced mortality ER, PR, and HER2 negative (7, 8).
rates (4). Mammography is the current gold standard Treatment strategies for BC are heavily influenced
for screening and biopsy, with definitive diagnosis by its underlying genetic makeup and associated
relying on pathological analysis (4). This analysis can biomarkers. Broadly, treatment regimens encompass
additionally identify various biomarkers expressed systemic chemotherapy alongside targeted therapies
within malignant tissues. Biomarkers hold immense like recombinant monoclonal antibodies and PARP
value in predicting disease course and prognosis (5). inhibitors (9). Compared to other BC subtypes, TNBC
BC classification hinges on a subtyping approach exhibits a poorer survival rate, a higher risk of
based on the expression levels of critical receptors:
estrogen receptor (ER), progesterone receptor (PR),

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168 Claudin-4 Antigen Overexpression in Breast Cancer Patients

recurrence, and a more challenging treatment course Windows® (version 20) software. Chi-square or
due to its limited targetability (10, 11). Mann-Whitney U tests were employed to analyze
Claudins, transmembrane proteins forming tight qualitative data, while independent T-tests evaluated
junctions between cells, play a vital role in regulating quantitative data. Five-year overall survival was
intercellular transport and maintaining epithelial cell estimated using comparative survival curves and
polarity (12, 13). Claudin 4 (CLDN4) is one of the Kaplan-Meier survival analysis with a log-rank test
significant CLDNs involved in tight junctions and is implemented in STATA® (version 14). A P-value of
associated with many different malignancies, as it can less than 0.05 was considered statistically significant.
influence the metastasis rate of malignancies. Its
overexpression has been reported in gastric (14), Results
pancreatic (15), colorectal (16), and BC (especially As shown in table-2, patients in the CLDN high
TNBC) (17, 18). Studies suggest that CLDN4 group and CLDN low group had no significantly
overexpression correlates with poor prognosis and different in case of mortality, recurrence, and
accelerated disease progression in these cancers. metastasis(P>0.05).
However, the precise impact of CLDN4 on long-term As depicted in Table 3, the log-rank test was
mortality in BC remains a subject of ongoing utilized to evaluate the outcomes. Model 1 was a crude
investigation and conflicting reports. Building upon a model, Model 2 was adjusted for the age at the time of
previous study that assessed CLDN4 overexpression in diagnosis, and Model 3 was adjusted for other
Isfahan's TNBC population, this current investigation covariates. No significant difference was observed in
delves into the long-term outcomes and mortality rates the 5-year overall survival, metastasis, and recurrence
associated with CLDN4 expression. rates for breast cancer between the two groups with
high and low CLDN expression. This observation
Materials and Methods remained consistent even after adjusting for age at
diagnosis, type of treatment, and other covariates
This retrospective study recruited participants
(Table 3).
previously diagnosed with TNBC in Isfahan, Iran.
Patients were categorized into two groups based on The hazard ratio (HR) for 5-year overall survival
CLDN4 expression levels, which were determined in a was 0.48 (95% CI = [0.13 – 1.27]) in the crude model.
prior investigation (Figure 1). Inclusion criteria When adjusted for age at the time of diagnosis, it
encompassed prior participation in the initial study and changed to 0.54 (95% CI = [0.20 – 1.43]), and to 0.58
obtaining informed consent. Incomplete patient (95% CI = [0.18-1.82]) when adjusted for other
records served as the sole exclusion criterion. covariates. In the model for metastasis, the HR was
0.64 (95% CI = [0.23-1.27]) in the crude model, 0.6
The study protocol was thoroughly explained to
(95% CI = [0.21-1.67]) when adjusted for age, and 0.52
patients or their designated next of kin after telephone
(95% CI = [0.15 – 1.52]) when adjusted for other
contact. Informed consent for participation was then
covariates. The HR for recurrence rates was 0.86 (95%
obtained from the participants themselves if they were
CI = [0.83-8.96]) in the crude model, 0.84 (95% CI =
alive, or from their immediate family if they had passed
[0.78-9.32]) when adjusted for age, and 0.83 (95% CI
away. Current health status was assessed, including
= [0.71-1.02]) when adjusted for other covariates.
deceased patients' cause and time of death.
Demographic and clinical data, including age at It should be noted that although CLDN4
diagnosis, tumor size and grade, lymph node overexpression, based on the HR, exhibited a protective
involvement, metastasis, Ki-67 index, and CLDN4 effect on survival, recurrence, and metastasis, it did not
expression, were retrieved from medical records. reach statistical significance due to the small sample size
and consideration of other covariates. A larger sample
In statistical analysis categorical data are presented
size makes statistical significance more likely to be
as frequencies with percentages (%), while scale data
achieved.
were expressed as means ± standard deviation (SD).
Statistical analysis was performed using SPSS® for

Table 1. Demographic and clinical variables. Chi-square was used for categorical and independent T-tests, and the Mann-Whitney
test was used for scale variables. Statistical significance is defined as having a p-value less than 0.05.
Characteristic CLDN high (n = 58) CLDN Low (n = 14) P-value
Age at diagnosis, mean year (SD) 54.3(11.6) 58.6(12.7) 0.223
Tumor grade, N (%)
Grade 1 2 (3.4) 2 (14.3)
Grade 2 15 (25.9) 3 (21.4) 0.281
Grade 3 41 (70.7) 9 (64.3)

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 Maryam Soltan et al. 169

Characteristic CLDN high (n = 58) CLDN Low (n = 14) P-value

Disease Stage, N (%)
1 16 (24.6) 6 (42.9)
2 25 (43.1) 4 (28.6) 0.154
3 13 (22.4) 1 (7.1)
4 4 (6.9) 3 (21.4)
Type of surgery received, N (%)
Lumpectomy 39 (67.2) 10 (71.4)
Mastectomy 19 (32.8) 4 (28.6) 0.517
No surgery 0 () 0 ()
lymph node involvement, N (%) 18 (31.0) 4 (28.6) 0.567
Tumor size (cm), N (%)
≤2 16 (27.6) 6 (42.9)
0.368
>2 42 (72.4) 8 (57.0)
Cancer history in the family, N (%)
No 30 (51.7) 6 (42.9)
Breast Cancer 15 (25.9) 3 (21.4) 0.587
Other cancers 13 (22.4) 5 (35.7)
Treatment type
Chemotherapy and radiotherapy 51 (87.9) 12 (85.7) 0.560
Chemotherapy 7 (12.1) 2 (14.3)
Ki-67 expression, mean % (±SD) 46.55(±20.2) 42.79(±20.2) 0.617
Disease history, N (%)
No history 37 (63.8) 11 (78.0)
0.234
CVD, hypertension, or diabetes 21 (34.5) 3 (21.4)

Table 2. Outcomes. Chi-square was used Statistical significance is defined as having a p-value less than 0.05.
Characteristic CLDN high (n = 58) CLDN Low (n = 14) p-value
Death, N (%) 14 (24.1) 6 (42.8) 0.143
Recurrence, N (%) 4 (6.9) 1 (7.1) 0.673
Metastasis, N (%) 15 (25.9) 5 (35.7) 0.333

Table 3. Multivariable analysis of breast cancer-specific 5-year overall survival, breast cancer metastasis, and breast cancer-
specific recurrence by Claudin expression status. Model 1 is crude; Model 2 is adjusted by age at the time of diagnosis and treatment
course; Model 3 is adjusted by age and other covariates, as described in Table 1. The hazard ratio is calculated using the log-rank
test, and statistical significance is defined as p < 0.05.
Model 1 Model 2 Model 3

Breast cancer-specific 5-year overall HR (%95 CI) 0.48 (0.13, 1.27) 0.54 (0.20, 1.43) 0.58 (0.18, 1.82)
survival P-value 0.123 0.806 0.338
HR (%95 CI) 0.64 (0.23, 1.27) 0.60 (0.21, 1.67) 0.52 (0.15, 1.52)
Breast cancer metastasis
P-value 0.203 0.331 0.409
HR (%95 CI) 0.86 (0.83, 8.96) 0.84 (0.78, 9.32) 0.83 (0.70, 10.2)
Breast cancer-specific recurrence
P-value 0.967 0.856 0.675

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170 Claudin-4 Antigen Overexpression in Breast Cancer Patients

Discussion
This study focused on the CLDN4 gene expression sample size (14 patients in the low CLDN4 group),
levels in previous BC patients. Patients were variable time intervals since diagnosis, and incomplete
categorized into two groups based on their CLDN4 access to clinical data. Socioeconomic factors also
expression. The findings revealed that the mortality played a role. Many patients belonged to lower
rate was significantly higher in the CLDN4 low- socioeconomic classes, resulting in infrequent follow-
expression group. However, neither group exhibits ups and incomplete treatment regimens for TNBC and
significant differences in demographic characteristics other co-morbidities, leading to unrelated mortality.
such as age, disease stage, tumor grade, treatment Furthermore, genetic differences within the Iranian
regimens employed, and Ki67 levels. Survival analysis population may be another contributing factor. Cancer
demonstrated that although the mortality rate was susceptibility and prognosis are heavily influenced by
higher in the CLDN4 low expression group, there was patient genetics. Prior studies have shown that ethnicity
no significant difference in the 5-year overall survival can impact five-year overall survival rates (26-28).
between the two groups, even after adjusting for Unfortunately, research on gene expression in the
covariates. Furthermore, survival analysis and hazard Iranian population remains limited, hindering robust
ratio for recurrence and metastasis also showed no conclusions. While the influence of ethnicity on
significant difference between the two groups. Our biomarker-prognosis associations remains unclear, we
study indicates that CLDN4 expression has no advocate for further studies exploring this topic within
significant impact on patients' 5-year overall survival, the Iranian population.
metastasis, or recurrence of BC.
CLDN4, a tight junction protein belonging to the
CLDN family, has emerged as a potential biomarker Conclusion
for malignant tumors. Prior in vivo studies have linked In conclusion, this retrospective study examining
CLDN4 overexpression to accelerated disease the impact of CLDN4 expression on long-term
progression, advanced staging, and poor prognosis in outcomes in triple-negative breast cancer patients from
BC cells. Ma et al. demonstrated that elevated CLDN4 Isfahan, Iran, did not find a significant association
expression in MCF-7 BC cell lines enhanced between CLDN4 levels and five-year overall survival,
proliferation and migration while reducing apoptosis metastasis, or recurrence rates. Although the mortality
(18). Conversely, Kolokytha et al. reported that rate was higher in the CLDN4 low expression group,
CLDN4 overexpression correlated with shorter the differences were not statistically significant after
disease-free survival and overall survival at five years, adjusting for potential confounders. These findings
specifically in TNBC patients, but only increased Ki- diverge from prior research linking CLDN4
67 proliferation index and tumor stage in luminal BC overexpression to poorer prognosis, potentially due to
patients (19). A critical distinction between our study limited sample size, incomplete data, and genetic
and Kolokytha et al.'s work lies in their focus on ductal variations within the Iranian population. Further larger-
carcinoma, whereas we recruited TNBC patients scale studies with standardized follow-up protocols and
irrespective of tumor location. consideration of ethnic differences are warranted to
clarify the prognostic value of CLDN4 in diverse
Abd-Elazeem et al. investigated CLDN4
populations and its potential utility as a biomarker for
overexpression in TNBC patients with primary invasive
personalized treatment strategies.
ductal carcinoma, identifying a positive and significant
correlation with age, tumor size, grade, lymph node
involvement, metastasis, and Ki-67 expression (20). Acknowledgments
Their findings further demonstrated that higher Ki-67, a None.
marker of poor prognosis, co-occurred with CLDN4
overexpression, suggesting CLDN4 as a valuable
prognostic indicator in TNBC. Szasz et al. bolstered the Ethical Approval
role of CLDN4 overexpression in TNBC prognosis by This cohort study was performed in line with the
highlighting its potent predictive power alongside principles of the Declaration of Helsinki. Approval was
CLDN3, CLDN7, and E-cadherin in survival analyses. granted by the Ethics Committee of Isfahan University
They reported that CLDN4 and E-cadherin accurately of Medical Sciences (IR.MUI.MED.REC.1401.355).
predicted relapse-free survival in a validation cohort at
five years, with efficacy across luminal and ductal
carcinomas (21). Additional studies have corroborated Funding/Support
the association between CLDN4 overexpression and This research received no specific grant from any
worse prognosis in TNBC patients (22-25). funding agency in the public, commercial, or not-for-
However, our findings diverge from previous profit sector.
research. We observed no correlation between CLDN4
overexpression and Ki-67, staging/grading, metastasis,
recurrence, or five-year overall survival rates. This
discrepancy might be partially attributed to our limited

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 Maryam Soltan et al. 171

Data Reproducibility Conflict of Interest

Data are available upon reasonable request from The authors declare no conflict of interest.
the corresponding author.

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