The MYC oncogene has protean effects on many biological processes, including gene transcription, protein translation, and DNA replication. These processes in turn coordinate many cellular functions, including proliferation, apoptosis, differentiation, self-renewal/senescence, and angiogenesis, as reviewed in this issue. The overexpression of MYC is one of the most common events associated with tumorigenesis, providing us with many reasons to consider that targeting this gene may be an effective treatment for human cancer.
Transgenic mouse models have been employed as a tractable approach for investigating the mechanism by which MYC and other oncogenes contribute to the initiation and maintenance of tumorigenesis.8–10
In particular, the development of conditional strategies for the regulation of gene expression in transgenic mouse models has been useful to define the circumstances under which oncogene inactivation will result in tumor regression (). It has become clear from these experiments in transgenic mouse models that the consequences of MYC inactivation are often dramatic and so result in sustained tumor regression. However, the specific mechanisms are contextual. Moreover, it has emerged that both tumor cell–intrinsic and host-dependent mechanisms are involved in oncogene addiction.1
Two major approaches have been used to generate conditional transgenic mouse models to dissect the role of MYC in the initiation and maintenance of tumorigenesis. The tetracycline system can be used to generate conditional transgenic models.13
In this model, a gene of interest is placed upstream of the tetracycline response element, and the tetracycline transactivating gene is placed upstream of a tissue-specific promoter. Transgenes of both constructs are generated, and mice that contain both transgenes express the gene of interest in a tissue-specific and temporally controlled manner. A similar strategy has been developed by utilizing a chimeric gene product between a gene of interest and the estradiol receptor.14
Here, the fusion gene exhibits conditional activity in the presence of tamoxifen. Both approaches have been used to demonstrate that the inactivation of a single oncogene can have profound effects on a tumor and in many cases result in a complete reversal of tumorigenesis in vivo
Conditional transgenic mouse models have demonstrated that MYC inactivation in tumors is associated with proliferative arrest, differentiation, senescence, and/or apoptosis (). Interestingly, the consequences of oncogene inactivation depend on the cellular and genetic context (). Most notably, the inactivation of the MYC oncogene has been shown to be potent in inducing tumor regression.14
MYC inactivation in lymphoma, leukemia, pancreatic islet cell tumors, and skin squamous carcinomas results in rapid tumor cell elimination through apoptosis.15
Many mouse models in which the MYC gene has been disrupted exhibit sustained tumor regression. In other tumor types, MYC inactivation appears to more generally induce terminal differentiation. For example, MYC inactivation in osteogenic sarcoma results in the terminal differentiation of tumor cells into mature bone cells.11
Note that these cells are now terminally differentiated and generally incapable of becoming tumor cells. Thus, even brief MYC inactivation can induce the sustained loss of a neoplastic phenotype.
Figure 1. MYC inactivation has different outcomes in different types of tumors, including proliferative arrest, differentiation, apoptosis, and/or cellular senescence. Although the consequences are different for each type of tumor, proliferative arrest, apoptosis, (more ...)
Figure 2. MYC inactivation elicits oncogene addiction by multiple mechanisms that differ depending on tumor type. MYC inactivation in lymphoma induces proliferative arrest, differentiation/senescence, and widespread apoptosis. Both tumor cell–intrinsic (more ...)
In contrast, brief inactivation of MYC fails to reverse tumorigenesis in epithelial tumors, such as hepatocellular carcinoma and breast cancer. In these contexts, some of these otherwise normal-appearing tumor cells can rapidly regain their neoplastic properties upon MYC reactivation.12,16
Hence, in this case, MYC inactivation is associated with the terminal differentiation of many of the tumor cells; in the case of hepatocellular carcinoma, the tumor cells can give rise to what appear to be normal liver cells, including hepatocytes and biliary cells. Yet, some of these cells retain the latent capacity to become tumor cells upon MYC reactivation. Thus, some tumor cells can, upon oncogene inactivation, appear normal and behave normally but actually be in a state of dormancy.17
In essence, sustained MYC inactivation results in tumor regression, but the reactivation of MYC can restore their neoplastic properties.
Genetic context has been shown to be critical in defining the consequence of the inactivation of MYC.7
Breast adenocarcinomas that have acquired a mutation in K-ras fail to undergo sustained regression upon MYC inactivation.18
Similarly, loss of p53 function markedly impedes the ability of MYC inactivation to induce sustained tumor regression.19
Snail has been identified as one gene product that appears to facilitate the escape from oncogene dependence.19
Loss of p53 function has also been shown to impede the sustained regression of lymphoma and leukemia through disruption of the ability of oncogene inactivation to induce the shutdown of angiogenesis.20
Finally, the escape from MYC inactivation induces the regression of hematopoietic tumors and appears to be associated with the acquisition of specific chromosomal translocations.21
Hence, there appear to be multiple genetic mechanisms that can predictably impede the ability of MYC inactivation to induce sustained tumor regression. One could speculate that these genetic events block MYC inactivation from inducing sustained regression solely because they prevent the triggering of oncogene addiction.