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 -