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Mol Cancer Ther. 2018 Jan;17(1):306-315. doi: 10.1158/1535-7163.MCT-17-0760. Epub 2017 Nov 13.

Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer.

Author information

1
The Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
2
Division of Molecular Pathology, Centre for Evolution and Cancer and Centre for Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
3
The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
4
Cancer Bioinformatics, Cancer Division, King's College London, London, United Kingdom.
5
Breast Cancer Now Research Unit, King's College London, London, United Kingdom.
6
Clinical Oncology, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, United Kingdom.
7
Department of Histopathology and Division of Cancer & Stem Cells, School of Medicine, The University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, United Kingdom.
8
The Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom. rachael.natrajan@icr.ac.uk.

Abstract

Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer-specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and γH2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. Mol Cancer Ther; 17(1); 306-15. ©2017 AACR.

PMID:
29133620
PMCID:
PMC6284786
DOI:
10.1158/1535-7163.MCT-17-0760
[Indexed for MEDLINE]
Free PMC Article

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