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Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response–targeted therapies in breast cancer

Naidoo, Kalnisha; Wai, Patty T.; Maguire, Sarah L.; Daley, Frances; Haider, Syed; Kriplani, Divya; Campbell, James; Mirza, Hasan; Grigoriadis, Anita; Tutt, Andrew; Moseley, Paul M.; Abdel-Fatah, Tarek M.A.; Chan, Stephen Y.T.; Madhusudan, Srinivasan; Rhaka, Emad A.; Ellis, Ian O.; Lord, Christopher J.; Yuan, Yinyin; Green, Andrew R.; Natrajan, Rachael

Authors

Kalnisha Naidoo

Patty T. Wai

Sarah L. Maguire

Frances Daley

Syed Haider

Divya Kriplani

James Campbell

Hasan Mirza

Anita Grigoriadis

Andrew Tutt

Paul M. Moseley

Tarek M.A. Abdel-Fatah

Stephen Y.T. Chan

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Christopher J. Lord

Yinyin Yuan

Rachael Natrajan



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.

Journal Article Type Article
Publication Date 2018-01
Journal Molecular Cancer Therapeutics
Print ISSN 1535-7163
Electronic ISSN 1538-8514
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 17
Issue 1
Pages 306-315
APA6 Citation Naidoo, K., Wai, P. T., Maguire, S. L., Daley, F., Haider, S., Kriplani, D., …Natrajan, R. (2018). Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response–targeted therapies in breast cancer. Molecular Cancer Therapeutics, 17(1), 306-315. doi:10.1158/1535-7163.mct-17-0760
DOI https://doi.org/10.1158/1535-7163.mct-17-0760
Keywords Cancer Research; Oncology
Publisher URL http://mct.aacrjournals.org/content/17/1/306
Additional Information This manuscript has been accepted for publication in Molecular Cancer Therapeutics, which is published by the American Association for Cancer Research

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