ArticleMolecular oncology2015
Untangling the ATR-CHEK1 network for prognostication, prediction and therapeutic target validation in breast cancer.
Article in Molecular oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 84 citations in OpenAlex.
- Synthetic Lethality-Based Targets and Their Exploration in Tumour Combination Strategies.Journal of cellular and molecular medicine · 2025Review
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- STEAP4 with copper reductase activity suppresses tumorigenesis by regulating the cell cycle in hepatocellular carcinoma cells.Cell division · 2024Article
- DNA damage response in breast cancer and its significant role in guiding novel precise therapies.Biomarker research · 2024Review
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- A new framework for exploratory network mediator analysis in omics data.Genome research · 2024Article
- Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers.International journal of molecular sciences · 2024Article
- Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets.Cancers · 2024Review
- The KRAS, ATR and CHEK1 expression levels in endometrial cancer are the risk factors predicting recurrence.PloS one · 2024Article
- Design, synthesis, and antitumor efficacy of novel 5-deazaflavin derivatives backed by kinase screening, docking, and ADME studies.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Dysfunction of ubiquitin protein ligaseNAR cancer · 2023Article
- Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis.International journal of molecular sciences · 2023Review
- Molecular Biology and Therapeutic Targets of Primitive Tracheal Tumors: Focus on Tumors Derived by Salivary Glands and Squamous Cell Carcinoma.International journal of molecular sciences · 2023Review
- Unravelling the clinicopathological and functional significance of replication protein A (RPA) heterotrimeric complex in breast cancers.NPJ breast cancer · 2023Article
- Natural products targeting the ATR-CHK1 signaling pathway in cancer therapy.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Review
- Hydrogen Sulfide Biology and Its Role in Cancer.Molecules (Basel, Switzerland) · 2022Review
- Prognostic Value of the Immunohistochemical Expression of RAD51 and BRCA2 in Gastric Adenocarcinoma.The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2022Article
- Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1.Frontiers in oncology · 2022Review
- MCM6 is a critical transcriptional target of YAP to promote gastric tumorigenesis and serves as a therapeutic target.Theranostics · 2022Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ATR-CHEK1 signalling is critical for genomic stability. ATR-CHEK1 signalling may be deregulated in breast cancer and have prognostic, predictive and therapeutic significance. We investigated ATR, CHEK1 and phosphorylated CHEK1 (Ser345) protein (pCHEK1) levels in 1712 breast cancers. ATR and CHEK1 mRNA expression was evaluated in 1950 breast cancers. Pre-clinically, biological consequences of ATR gene knock down or ATR inhibition by the small molecule inhibitor (VE-821) were investigated in MCF7 and MDA-MB-231 breast cancer cell lines and in non-tumorigenic breast epithelial cells (MCF10A). High ATR and high cytoplasmic pCHEK1 levels were significantly associated with higher tumour stage, higher mitotic index, pleomorphism and lymphovascular invasion. In univariate analyses, high ATR and high cytoplasmic pCHEK1 levels were associated with poor breast cancer specific survival (BCSS). In multivariate analysis, high ATR level remains an independent predictor of adverse outcome. At the mRNA level, high CHEK1 remains associated with aggressive phenotypes including lymph node positivity, high grade, Her-2 overexpression, triple negative, aggressive molecular phenotypes and adverse BCSS. Pre-clinically, CHEK1 phosphorylation at serine(345) following replication stress was impaired in ATR knock down and in VE-821 treated breast cancer cells. Doxycycline inducible knockdown of ATR suppressed growth, which was restored when ATR was re-expressed. Similarly, VE-821 treatment resulted in a dose dependent suppression of cancer cell growth and survival (MCF7 and MDA-MB-231) but was less toxic in non-tumorigenic breast epithelial cells (MCF10A). We provide evidence that ATR and CHEK1 are promising biomarkers and rational drug targets for personalized therapy in breast cancer.
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