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

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ICR Authors

Naidoo, Kalnisha
 Haider, Syed
 Campbell, James
 Tutt, Andrew
 Lord, Christopher
 Yuan, Yinyin
 Natrajan, Rachael

Authors

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

Document Type

Journal Article

Date

2018-01-01

Date Accepted

2017-10-19

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.

Citation

Molecular cancer therapeutics, 2018, 17 (1), pp. 306 - 315

DOI

10.1158/1535-7163.mct-17-0760

URI

https://repository.icr.ac.uk/handle/internal/849

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

AMER ASSOC CANCER RESEARCH

ISSN

1535-7163

eISSN

1538-8514

Collections

Breast Cancer Research
Cancer Biology

Research Team

Target Validation and DNA Damage Response
Computational Pathology & Integrated Genomics
Functional Genomics
Gene Function

Notes