Abstract
IntroductionTargeted therapies for aggressive breast cancers like triple negative breast cancer (TNBC) are needed. The use of small interfering RNAs (siRNAs) to disable expression of survival genes provides a tool for killing these cancer cells. Cyclin dependent kinase 11 (CDK11) is a survival protein kinase that regulates RNA transcription, splicing and mitosis. Casein kinase 2 (CK2) is a survival protein kinase that suppresses cancer cell death. Eliminating the expression of these genes has potential therapeutic utility for breast cancer.MethodsExpression levels of CDK11 and CK2 mRNAs and associated proteins were examined in breast cancer cell lines and tissue arrays. RNA expression levels of CDC2L1, CDC2L2, CCNL1, CCNL2, CSNK2A1, CSNK2A2, and CSNK2B genes in breast cancer subtypes were analyzed. Effects following transfection of siRNAs against CDK11 and CK2 in cultured cells were examined by viability and clonal survival assays and by RNA and protein measures. Uptake of tenfibgen (TBG) nanocapsules by TNBC cells was analyzed by fluorescence-activated cell sorting. TBG nanocapsules delivered siRNAs targeting CDK11 or CK2 in mice carrying TNBC xenograft tumors. Transcript cleavage and response parameters were evaluated.ResultsWe found strong CDK11 and CK2 mRNA and protein expression in most human breast cancer cells. Immunohistochemical analysis of TNBC patient tissues showed 100% of tumors stained positive for CDK11 with high nuclear intensity compared to normal tissue. The Cancer Genome Atlas analysis comparing basal to other breast cancer subtypes and to normal breast revealed statistically significant differences. Down-regulation of CDK11 and/or CK2 in breast cancer cells caused significant loss of cell viability and clonal survival, reduced relevant mRNA and protein expression, and induced cell death changes. TBG nanocapsules were taken up by TNBC cells both in culture and in xenograft tumors. Treatment with TBG- siRNA to CDK11 or TBG- siRNA to CK2αα’ nanocapsules induced appropriate cleavage of CDK11 and CK2α transcripts in TNBC tumors, and caused MDA-MB-231 tumor reduction, loss of proliferation, and decreased expression of targeted genes.ConclusionsCDK11 and CK2 expression are individually essential for breast cancer cell survival, including TNBC. These genes serve as promising new targets for therapeutic development in breast cancer.
Highlights
Targeted therapies for aggressive breast cancers like triple negative breast cancer (TNBC) are needed
Cyclin dependent kinase 11 (CDK11) and Casein kinase 2 (CK2) expression are individually essential for breast cancer cell survival, including TNBC
We examined the steady-state protein expression levels for CDK11 and CK2 protein complex members in breast cancer cell lines representing a range of subtypes
Summary
Targeted therapies for aggressive breast cancers like triple negative breast cancer (TNBC) are needed. Given the need for new approaches to treat TNBC, we investigated the effectiveness of downregulation of the essential protein kinases cyclindependent kinase (CDK) 11 and casein kinase 2 (CK2) using RNA interference (RNAi) for killing this aggressive form of breast cancer. When targeting a survival gene, an RNAi or small interfering RNA (siRNA) approach to downregulate or eliminate the survival protein expression, and its function, has advantages of great flexibility and specificity in choosing the target. The difficulty in such an approach when moving to systemic organismal use comes with delivery of the nucleic acids in a protected and tumor-directed manner. Gene mutation does not play a significant role in CDK11 function in cancer, and the majority of mutations reported are missense, suggesting again the essential nature of CDK11 function (Sanger COSMIC database)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
