Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer.
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Date
2018-01-01ICR Author
Author
Naidoo, K
Wai, PT
Maguire, SL
Daley, F
Haider, S
Kriplani, D
Campbell, J
Mirza, H
Grigoriadis, A
Tutt, A
Moseley, PM
Abdel-Fatah, TMA
Chan, SYT
Madhusudan, S
Rhaka, EA
Ellis, IO
Lord, CJ
Yuan, Y
Green, AR
Natrajan, R
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Breast Neoplasms
DNA Damage
Cyclin-Dependent Kinases
Immunohistochemistry
Retrospective Studies
Middle Aged
Female
Biomarkers, Tumor
Research team
Target Validation and DNA Damage Response
Computational Pathology & Integrated Genomics
Functional Genomics
Gene Function
Language
eng
Date accepted
2017-10-19
License start date
2018-01
Citation
Molecular cancer therapeutics, 2018, 17 (1), pp. 306 - 315
Publisher
AMER ASSOC CANCER RESEARCH