Chk1 as a new therapeutic target in triple-negative breast cancer.

Abstract

OBJECTIVES:

Bioinformatics analyses of pathways and genes differentially expressed between malignant and benign lesions could allow discovering new therapeutic targets. Here, we identified Checkpoint kinase 1 (Chk1) as a potent therapeutic target in triple-negative breast cancer (TNBC).

MATERIALS AND METHODS:

Differential gene expression between TNBC, other malignant and benign lesions was performed on two breast cancer datasets. Chk1 was targeted using RNA interference or chemical inhibitor in several TNBC cell lines.

RESULTS:

DNA repair pathway was identified as one mostly deregulated pathway in TNBC as compared to benign lesions. Chk1 was identified as candidate target among the 35 genes included in this pathway. Gene expression analysis revealed that Chk1 gene was significantly overexpressed in TNBC as compared to non-TNBC and benign lesions. Depletion of Chk1 protein expression induced a marked reduction of cell viability and led to mitotic catastrophe in TNBC cells. Chemical Chk1 inhibitor decreased survival in TNBC cells, and transcriptome analyze revealed a modulation of gene expression profile in response to Chk1 treatment.

CONCLUSION:

These findings suggest that Chk1 may represent a therapeutic target in TNBC, and provide a rationale to evaluate Chk1 inhibitors in breast cancer patients.

• Authors: Laurence Albiges, Aïcha Goubar, Véronique Scott, Cécile Vicier, Céline Lefèbvre, Samar Alsafadi, Frédéric Commo, Mahasti Saghatchian, Vladimir Lazar, Philippe Dessen, Suzette Delaloge, Fabrice André, Virginie Quidville
• Journal: Breast (Edinburgh, Scotland) (Breast) Vol. 23 Issue 3 Pg. 250-8 (Jun 2014) ISSN: 1532-3080 [Electronic] Netherlands
• PMID: 24636978 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Checkpoint Kinase 1
• DNA Repair (drug effects)
• Drug Repositioning
• Female
• Gene Expression Profiling
• Gene Knockdown Techniques (methods)
• Humans
• Molecular Targeted Therapy
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (genetics)
• RNA Interference
• Triple Negative Breast Neoplasms (genetics, therapy)