Dataset Information

The Presence of EpCAM(-)/CD49f(+) Cells in Breast Cancer Is Associated with a Poor Clinical Outcome.

ABSTRACT:

Purpose

It is well established that breast cancer stem cells (BCSCs) play an essential role in tumor invasion for both local and distant metastasis. The aim of this study was to establish whether BCSCs could act as a prognostic and clinical marker.

Methods

We analyzed tumor tissues from 161 breast cancer patients. Dual immunohistochemistry and immunofluorescence were performed on all the slides, and we analyzed the relationship between EpCAM(-)/CD49f(+) tumor cells and key clinical and prognostic factors.

Results

Univariate survival analysis using the Kaplan-Meier method showed that the presence of EpCAM(-)/CD49f(+) tumor cells in breast cancer was significantly associated with shorter disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that the presence of EpCAM(-)/CD49f(+) cells was associated with shorter DFS (p=0.010; hazard ratio [HR], 2.070) and OS (p=0.002; HR, 3.235). Tumors containing EpCAM(-)/CD49f(+) cells were also more likely to metastasize after initial surgery (p=0.048).

Conclusion

Our study suggests that breast tumors containing EpCAM(-)/CD49f(+) cells are more likely to undergo distant metastasis after initial surgery and are associated with a shorter DFS and OS.

SUBMITTER: Ye F

PROVIDER: S-EPMC4600688 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

The Presence of EpCAM(-)/CD49f(+) Cells in Breast Cancer Is Associated with a Poor Clinical Outcome.

Ye Feng F Qiu Yan Y Li Li L Yang Libo L Cheng Fei F Zhang Hongying H Wei Bing B Zhang Zhang Z Sun Linyong L Bu Hong H

Journal of breast cancer 20150924 3

<h4>Purpose</h4>It is well established that breast cancer stem cells (BCSCs) play an essential role in tumor invasion for both local and distant metastasis. The aim of this study was to establish whether BCSCs could act as a prognostic and clinical marker.<h4>Methods</h4>We analyzed tumor tissues from 161 breast cancer patients. Dual immunohistochemistry and immunofluorescence were performed on all the slides, and we analyzed the relationship between EpCAM(-)/CD49f(+) tumor cells and key clinica ...[more]

PMID: 26472974

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Project description:IntroductionCancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists.Materials and methodsWe performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation.ResultsPranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC.ConclusionOur results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.

Dataset Information

The Presence of EpCAM(-)/CD49f(+) Cells in Breast Cancer Is Associated with a Poor Clinical Outcome.

Purpose

Methods

Results

Conclusion

Publications

The Presence of EpCAM(-)/CD49f(+) Cells in Breast Cancer Is Associated with a Poor Clinical Outcome.

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