CDK12 IS A NOVEL ONCOGENE WITH CLINICAL AND PATHOGENETIC RELEVANCE IN BREAST CANCER

Breast cancer heterogeneity demands new reliable prognostic markers and therapeutic targets for the personalized management of patients. Over recent years, knowledge on the involvement of different types of kinases in cancer has guided the design of a variety of kinase inhibitors as novel molecularly targeted anti-cancer agents. In a previous high-throughput screening performed by in situ hybridization (ISH) and immunohistochemistry (IHC) on breast cancer tissue microarrays (TMAs), the cyclin-dependent kinase 12 (CDK12) was found to be frequently overexpressed in breast cancer and its overexpression correlated with clinical/pathological parameters of aggressive disease. CDK12 was therefore proposed to be a novel prognostic biomarker in breast cancer. In the present thesis, we extend these preliminary studies and demonstrate, by IHC analysis on TMAs comprising large cohorts of breast cancer patients, that CDK12 overexpression is significantly associated with clinical/pathological parameters of poor prognosis (high tumor grade, high Ki67 proliferative index, positive ERBB2 status) and with a higher risk of disease recurrence and death. We also show, either in human breast tumors or in breast cancer cell lines, that CDK12 overexpression is due to the amplification of the CDK12 gene. Through the use of amenable cell models in diverse in vitro and in vivo assays, we provide evidences that CDK12 is a bona fide oncogene in breast cancer. By genome-wide expression analysis, we show that alterations in CDK12 expression are associated with changes in the transcription and splicing of genes involved in cancer-relevant cellular processes, such as DNA damage response, cell cycle and epithelial-to-mesenchymal transition. In conclusion, we have established that CDK12 is a novel prognostic biomarker in breast cancer and represents a potential novel molecular target for therapeutic intervention in breast cancer.