CMyc Deregulation in Cancer

c-Myc overexpression is associated with neoplasms of different tissues, including breast (11,12), neuroblastoma (13), cervical carcinoma (14), malignant melanoma (15), prostate cancer (16), osteogenic sarcoma (17), and lymphoid cancer (6, 18, 19); (reviewed in 20). Thus, Myc protein overexpression is an important player in cellular transformation (21-25).

Myc Deregulation

Neoplasia

Figure 1. c-Myc-dependent locus-specific and karyotypic instability in neoplasia.

Neoplasia

Figure 1. c-Myc-dependent locus-specific and karyotypic instability in neoplasia.

Locus-specific Genomic Instability. c-Myc induces the instability of some genes, but not of others. Therefore, we generated the term 'locus-specific' genomic instability (Figure 1). This type of instability was first described in the report that the dihydrofolate reductase (DHFR) gene was amplified as a result ofinducible c-myc overexpression (26, 27). DHFR was amplified within 72 h of inducible c-Myc deregulation in a variety of cell lines of mouse, hamster, and human origin, and in several tissue types. The amplification of DHFR was reversible when c-Myc was induced transiently (27). In the same cells, however, other genes, such as cyclin C, ribonucleotide reductase R1, syndecan-1, and glyceraldehyde phosphate dehydrogenase (GAPDH) did not show genomic instability.

Subsequently, in-vivo studies showed that DHFR was amplified in primary mouse plasmacytomas, Myc-dependent B lymphocytic tumors that develop in susceptible mice, such as BALB/c (28). If DHFR amplification were an early event in c-Myc-induced tumorigenesis, one would expect to find evidence of DHFR instability early in tumorigenesis. Indeed, plasmacytoma induction studies showed that DHFR was amplified within the first week of c-myc deregulation (29) (Figure 2). The amplification of the DHFR gene occurred intra-and extra-chromosomally in mouse and human cells, however only intra-chromosomally in the hamster cell line CHO-9.

Subsequently, additional genes were shown to lose stability when c-myc expression was deregulated. Among them are: ribonucleotide reductase R2 (R2) (30), cyclin D2 (31), ODC (32) and CAD (33). All of these genes are amplified intra- and extra-chromosomally in the presence ofconstitutive c-myc expression. c-Myc-dependent induction of extra-chromosomally amplified genes is a novel product of c-Myc-dependent genomic instability. Several genes can be found in these extra-chromosomal elements. These genes carry histones and are able to replicate, thus behaving as functional genetic units (34). The generation of these extra-chromosomal elements may occur via illegitimate replication, DNA breakage, and/or DNA recombination (see additional discussion below).

Figure 2. c-Myc-dependent amplification of DHFR. Fluorescent in-situ hybridization (FISH) demonstrates that the DHFR gene is amplified in a mouse plasmacytoma.

A. Part of a metaphase showing a large double minute chromosome (arrow).

B. Same as A showing DHFR and some pieces of cyclin B1 on the double minute chromosome. DHFR is shown in red, cyclin B1 in green. Chromosomes are counterstained with DAPI (blue). (Figure may be viewed in color at http://springeronline.com/0-387-23783-6)

Karyotypic Instability. c-myc deregulation also induces karyotypic instability (35, 36). This form of genomic instability was found in cell lines after prolonged c-myc deregulation (35). In addition, when injected into nude mice, cells that constitutively expressed c-myc developed karyotypic instability (36). The types of instability seen in vivo were identical to those seen in vitro: aneuploidy, telomere-centromere fusions, chromosome breakage, formation of unstable ring chromosomes, and generation of extra-chromosomal elements.

Long-range Illegitimate Recombinations, c-myc deregulation in murine B-cell lymphomas has been shown to induce recombination events that involved many different chromosomes (37). These illegitimate recombinations included translocations, deletions and inversions. DNA sequencing and spectral karyotyping showed that a wide variety of chromosomal regions had been affected and many different break points involved. Recent studies have also examined whether c-myc deregulation also increased the rate of point mutations or large-scale rearrangements. Davis, et al. (38) did not observe increased mutation rates in Myc-induced liver cancers, and Rockwood, et al. (37) reported no significant increase in point mutations in mouse Burkitt lymphoma with c-myc deregulation. However, Partlin, et al. (39) described a small increase in HGPRT mutations as a result of c-myc deregulation in Rat1a fibroblasts. The differences in these data may lie in the different cell systems used. Further studies are needed to clarify this point.

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