Research Article: Differential Impact of Tumor Suppressor Pathways on DNA Damage Response and Therapy-Induced Transformation in a Mouse Primary Cell Model

Date Published: January 1, 2010

Publisher: Public Library of Science

Author(s): A. Kathleen McClendon, Jeffry L. Dean, Adam Ertel, Erik S. Knudsen, Mikhail V. Blagosklonny.

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.

Partial Text: The response to genotoxic stress is a critical event that has broad implications to cancer. It is well appreciated that a number of environmental carcinogens act through the induction of DNA damage to promote tumor initiation [1], [2]. For example, Aflatoxin B1 elicits oxidative damage and is a key etiological factor for hepatocellular carcinoma [3], and exposure to solar radiation is a key risk factor for skin cancer [4]. While genotoxic agents are strongly linked to tumorigenesis, the cytotoxic effect of DNA damage is also a critical facet of cancer therapy. In fact, the majority of human tumors are treated using agents that are genotoxic compounds. A major caveat of such therapies is the possibility of inducing secondary primary malignancies, or exacerbating existing disease by promoting genomic instability or facilitating selection of aggressive, therapy-resistant forms of disease [5]. Clearly, understanding genetic alterations that influence these responses is critical for efficacious cancer treatment.

Cancer is one of many diseases that arise from multiple genetic and epigenetic alterations within a cell [2], [46], [47], [48]. Here, we dissected how two commonly inactivated tumor suppressors function in the response to therapy-induced damage and examined the consequence of such challenge in terms of oncogenic behavior and therapeutic resistance.



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