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CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15-20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic. Little is known about CLDN1 role on the chemosensitivity of breast cancer. Our clinical data analysis reveals that CLDN1 low expression is correlated to a poor prognostic in TNBC patients. Next, the sensitivity of various TNBC "claudin-1-high" or "claudin-1-low" cells to three compounds belonging to the main class of chemotherapeutic agents commonly used for the treatment of TNBC patients: 5-fluorouracil (5-FU), paclitaxel (PTX) and doxorubicin (DOX). Using RNA interference and stable overexpressing models, we demonstrated that CLDN1 expression increased the sensitivity of TNBC cell lines to these chemotherapeutic agents. Taken together, our data established the important role of CLDN1 in TNBC cells chemosensitivity and supported the hypothesis that CLDN1 could be a chemotherapy response predictive marker for TNBC patients. This study could allow new treatment protocols creation aimed to induce CLDN1 expression in TNBCs to increase their sensitivity to chemotherapy.

SUBMITTER: Lemesle M

PROVIDER: S-EPMC9599637 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

Lemesle Marine M Geoffroy Marine M Alpy Fabien F Tomasetto Catherine-Laure CL Kuntz Sandra S Grillier-Vuissoz Isabelle I

Cancers 20221014 20

Triple-negative breast cancer (TNBC) is an aggressive subtype that constitutes 15-20% of breast cancer cases worldwide. Current therapies often evolve into chemoresistance and lead to treatment failure. About 77% of the TNBC lacks claudin-1 (CLDN1) expression, a major tight junction component, and this absence is correlated with poorer prognostic. Little is known about CLDN1 role on the chemosensitivity of breast cancer. Our clinical data analysis reveals that CLDN1 low expression is correlated ...[more]

PMID: 36291810

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Project description:IntroductionTriple-negative breast cancer (TNBC) is a heterogeneous disease with no definitive prognostic markers. As a major component of tight junctions, claudins (CLDNs) presumably play an important role in carcinogenesis and progression of breast cancer. This study was aimed at determining the relationship between the expression of CLDNs and the clinical outcomes of TNBCs.Materials and methodsThe surgical specimens of primary breast tumors from a consecutive cohort of 173 TNBC patients were retrospectively collected. The membranous expression of CLDN1, CLDN2, CLDN4, and CLDN7 was measured by immunohistochemistry. Then, the associations between CLDN expression, clinicopathological features, and clinical outcomes were assessed.ResultsPositive CLDN1, CLDN2, CLDN4, and CLDN7 membrane expression was detected in 44.5%, 54.9%, 76.9%, and 73.4% of the cohort specimens, respectively. A lack of CLDN1 expression was related to only lymph node metastasis (P = 0.014). The rate of CLDN4-positive tumors was significantly increased in tumors of a higher grade (P = 0.003). Importantly, negative CLDN1 expression was associated with worse relapse-free survival (RFS) in both lymph node positive (LN+) and negative (LN-) cases (both P<0.001). Similarly it was also associated with shorter overall survival (OS)(P = 0.003 in LN+ cases; P = 0.018 in LN- cases). In the LN+ subgroup, CLDN2-negative cases had a significantly higher risk of recurrence (P = 0.008). Multivariate analysis revealed that negative CLDN1 expression was an independent prognostic factor for high risk of both recurrence and death (HR 5.529, 95% CI 2.664-11.475, P<0.001; HR 3.459, 95% CI 1.555-7.696, P = 0.002). However, neither CLDN4 nor CLDN7 expression was associated with survival.ConclusionIn TNBC, the CLDN1-negative phenotype predicts a high risk of recurrence and death. The absence of CLDN1 expression is strongly suggested to be an independent adverse prognostic factor in this heterogeneous subtype of breast cancer.

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CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

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CLDN1 Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy.

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