Title: Differential impact of tumor suppressor pathways on DNA damage response and therapy-induced transformation in a mouse primary cell model.

Authors: McClendon, A Kathleen; Dean, Jeffry L; Ertel, Adam; Knudsen, Erik S

Published In PLoS One, (2010 Jan 01)

Abstract: The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease.

PubMed ID: 20049321

MeSH Terms: Animals; Base Sequence; Blotting, Western; Cell Cycle; Cell Transformation, Neoplastic*; Cells, Cultured; DNA Damage*; DNA Primers; Genes, Retinoblastoma; Genes, Tumor Suppressor*; Genes, p53; Mice; Models, Biological*; Mutation; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction