c-Myc: Linking Transformation and Genomic Instability

Abstract

CMYC has long been known to be among the most frequently de-regulated oncogenes in human cancer. Only recently, however has a clear understanding begun to emerge of how it promotes transformation. Through its role as a transcription factor, c-Myc alters the expression of hundreds of target genes, many of which are themselves oncogenes or tumor suppressors. The deregulation of c-Myc is both necessary and sufficient for the "acute" type of rapid in vitro transformation that occurs in certain established rodent cell lines. Transformation of primary rodent cells in vitro is also rapid but requires the contribution of at least one additional cooperating oncogene such as Ras. In contrast, the "chronic" form of in vivo transformation by c-Myc is a rare event that requires the acquisition of multiple mutations in other genes affecting cell cycle, senescence, and apoptosis. By greatly accelerating the intrinsic mutation rate at several levels, c-Myc increases the likelihood that these additional mutational "hits" will occur. Among the types of genomic instability mediated by c-Myc are single nucleotide substitutions and double-stranded breaks arising via the induction of reactive oxygen species, gene amplification and the generation of extrachromosomal elements, and numerical chromosomal defects resulting from aberrant DNA synthesis and defects in the mitotic spindle checkpoint. These non-mutually exclusive activities ensure a constant and varied source of genotoxic insults and suggest that c-Myc over-expression imposes a "mutator phenotype". This may be an early and necessary requirement for the initial steps in chronic transformation as well as for subsequent evolutionary changes that produce important tumor behaviors such as invasiveness, metastasis, and acquisition of chemotherapy resistance.

c-MYC-Induced Genomic Instability

“…2) (Mai et al 1996a;Felsher and Bishop 1999b;Rockwood et al 2002;Guffei et al 2007; Gonçalves Dos Santos Silva et al 2008;Silva et al 2010;Chen et al 2011). Recent reviews have addressed this role of MYC in instability (Dang et al 2005;Prochownik and Li 2007;Prochownik 2008). Also, genome-wide approaches have highlighted MYC's overall potential to impact the genomic stability of the cell (Neiman et al 2006(Neiman et al , 2008.…”

“…PRDX3, which plays an important role in protection of ROS produced in hypoxic conditions, is also a target gene of MYC in Rat1a cells (Wonsey et al 2002). Additional genes involved in ROS and regulated by MYC have been reviewed by Prochownik (2008). In in vivo studies, using a transgenic mouse model of hepatocarcinogenesis, overexpression of TGF-a and c-MYC led to chronic oxidative stress followed by impaired DNA damage response, genomic instability, and, ultimately, tumor progression (Hironaka et al 2003).…”

The Animal Within: Carcinogenesis and the Clonal Evolution of Cancer Cells Are Speciation Events Sensu Stricto

“…Fraser et al seem to accept the concept of speciation in bacteria, providing that clustering underpinned by some level of sexual isolation, occurs (Fraser et al 2007). This implies, for cancer, to the extent a mutator phenotype exists (Sarasin 2003;Loeb et al 2008;Prochownik 2008), that beyond some point of evolved diversity, secondary speciation thresholds must be crossed. Doolittle and Papke (2006) took the interesting stance that bacterial species may exist, but the boundaries of species are not necessarily sharp.…”

Dérèglements cellulaires et moléculaires à l’origine du phénotype métastatique

“…La perte des capacités de liaison avec la β-caténine entraîne une accumulation nucléaire et une activation transcriptionnelle constitutive du gène MYC. De fait, la surexpression de β-caténine nucléaire sur le front d'invasion et dans les vaisseaux est prédictive du risque de métastases hépatiques et la surexpression de c-Myc impose un « phénotype mutationnel » précoce nécessaire à l'acquisition de la capacité métastatique et de chimiorésistance [9,10].…”

“…L'absence de valeur pronostique indépendante du 8q s'explique par le lien étroit entre APC (gène effecteur) et MYC (gène cible) dans la voie Wnt. Notre hypothèse est qu'une coopération entre les altérations du 8q et du 5q optimise l'effet dose de la protéine Myc, essentielle dans la régulation de l'autonomie des cellules souches et l'apoptose, expliquant son haut pouvoir de transformation en cellule souche cancéreuse en cas de surdosage [10,14].…”