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

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.

Citation

Naidoo, K., Wai, P. T., Maguire, S. L., Daley, F., Haider, S., Kriplani, D., Campbell, J., Mirza, H., Grigoriadis, A., Tutt, A., Moseley, P. M., Abdel-Fatah, T. M., Chan, S. Y., Madhusudan, S., Rhaka, E. A., Ellis, I. O., Lord, C. J., Yuan, Y., Green, A. R., & 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. https://doi.org/10.1158/1535-7163.mct-17-0760

• Journal Article Type: Article
• Acceptance Date: Oct 19, 2017
• Online Publication Date: Nov 13, 2017
• Publication Date: 2018-01
• Deposit Date: Oct 12, 2018
• Publicly Available Date: Nov 14, 2018
• 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
• DOI: https://doi.org/10.1158/1535-7163.mct-17-0760
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/1163384
• 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
• Contract Date: Oct 16, 2018