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Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer.

ABSTRACT: Using whole transcriptome analysis and a lentiviral short hairpin RNA screening library, carboxypeptidase A4 (CPA4) was identified as a novel marker in breast cancer and a therapeutic target in triple?negative breast cancer (TNBC) in the present study. Immunohistochemistry was used to evaluate the presence of CPA4, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki67, epidermal growth factor receptor, cytokeratin 5/6, aldehyde dehydrogenase 1, cluster of differentiation (CD)44, CD24, claudins, E?cadherin, vimentin and androgen receptor in 221 cases of breast cancer, including 68 TNBC cases. The effects of CPA4 on the viability and migration ability of TNBC cells were analyzed using RNA interference methods. Increased CPA4 expression, specifically in the cytoplasm of cancer tissue cells, was detected. Furthermore, high CPA4 expression in TNBC cases was associated with low expression of E?cadherin and with the expression of cancer stem cell markers (high CD44/low CD24). Patients with TNBC and high levels of CPA4 expression had a significantly poorer prognosis compared with those with low CPA4 expression. Notably, viability and migration were reduced, but E?cadherin expression was upregulated in CPA4?suppressed TNBC cells. The present data suggested that CPA4 may be a novel inducer for epithelial?mesenchymal transition, which is characterized by the downregulation of E?cadherin and mesenchymal phenotypes. To conclude, CPA4 may be a marker for poor prognosis and a promising therapeutic target in TNBC with aggressive phenotypes.

SUBMITTER: Handa T

PROVIDER: S-EPMC6365037 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer.

Handa Tadashi T Katayama Ayaka A Yokobori Takehiko T Yamane Arito A Fujii Takaaki T Obayashi Sayaka S Kurozumi Sasagu S Kawabata-Iwakawa Reika R Gombodorj Navchaa N Nishiyama Masahiko M Asao Takayuki T Shirabe Ken K Kuwano Hiroyuki H Oyama Tetsunari T

International journal of oncology 20190104 3

Using whole transcriptome analysis and a lentiviral short hairpin RNA screening library, carboxypeptidase A4 (CPA4) was identified as a novel marker in breast cancer and a therapeutic target in triple‑negative breast cancer (TNBC) in the present study. Immunohistochemistry was used to evaluate the presence of CPA4, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki67, epidermal growth factor receptor, cytokeratin 5/6, aldehyde dehydrogenase 1, cluster of diffe ...[more]

PMID: 30628666

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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.

Dataset Information

Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer.

Publications

Carboxypeptidase A4 accumulation is associated with an aggressive phenotype and poor prognosis in triple-negative breast cancer.

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