Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy

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Abstract

Introduction: Targeted 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. Methods: Expression 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. Results: We 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. Conclusions: CDK11 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.

Original languageEnglish (US)
Article number19
JournalBreast Cancer Research
Volume17
Issue number1
DOIs
StatePublished - Feb 11 2015

Bibliographical note

Funding Information:
This work was supported by the Minnesota Veterans Medical Research and Education Foundation (JHT); Merit Review research funds (1IO1B001731) awarded by the Department of Veterans Affairs (KA); research grant CA150182 awarded by the National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (KA); research grants CA158730 and DK067436 awarded by National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases, respectively, NIH, Department of Health and Human Services (BTK); and research grants HHS-N261-2008-00027/N42CM-2008-00027C, CA99366, and CA119556 awarded by National Cancer Institute, NIH, Department of Health and Human Services (GMU).

Publisher Copyright:
© Kren et al.

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