Targeted and systemic insights into the crosstalk between DNA-dependent protein kinase catalytic subunit and receptors of estrogen, progesterone and epidermal growth factor in the context of cancer

Abstract

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has emerged as a regulator of carcinogenesis. Increased expression of DNA-PKcs correlates with metastatic cancers. Here we review recently reported crosstalk of DNA-PKcs with estrogen (ER), progesterone (PR) and epidermal growth factor (EGFR) receptors. The reports show an extensive network of functional and direct interactions. Targeted studies focused on specific molecular mechanisms, and a systems biology network analysis shows unbiasedly engagement of various cellular functions. Feedforward regulation between expression and activities of DNA-PKcs and ER, DNA-PKcs-dependent phosphorylation of PR and an impact on PR-dependent transcription, and DNA-PKcs-promoted EGFR-dependent aggressiveness and metastases are examples of the results of targeted studies. Systems biology approach extracted many more genes and proteins engaged by DNA-PKcs in interaction with ER, PR, and EGFR. Examples are such regulators and predictors of breast tumorigenesis as BRCA1, TP53, and 18 genes of the MammaPrint signature. Reviewed here data suggest that the diagnostic value of DNA-PKcs in the context of ER, PR and EGFR signaling is defined by a network signature rather than by single markers. This review summarizes mechanisms of DNA-PKcs interaction with ER, PR, and EGFR, highlights tumor suppressors and oncogenes engaged by DNA-PKcs, and emphasizes the importance of diagnostic network-based signatures.