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

TY - JOUR

T1 - Evaluation of CDK12 protein expression as a potential novel biomarker for DNA damage response-targeted therapies in breast cancer

AU - Naidoo, Kalnisha

AU - Wai, Patty T.

AU - Maguire, Sarah L.

AU - Daley, Frances

AU - Haider, Syed

AU - Kriplani, Divya

AU - Campbell, James

AU - Mirza, Hasan

AU - Grigoriadis, Anita

AU - Tutt, Andrew

AU - Moseley, Paul M.

AU - Abdel-Fatah, Tarek M.A.

AU - Chan, Stephen Y.T.

AU - Madhusudan, Srinivasan

AU - Rhaka, Emad A.

AU - Ellis, Ian O.

AU - Lord, Christopher J.

AU - Yuan, Yinyin

AU - Green, Andrew R.

AU - Natrajan, Rachael

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040071745&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-17-0760

DO - 10.1158/1535-7163.MCT-17-0760

M3 - Article

AN - SCOPUS:85040071745

SN - 1535-7163

VL - 17

SP - 306

EP - 315

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 1

ER -