MYC P53 INTERACTIONS IN TRANSGENIC MOUSE MAMMARY DEVELOPMENT, TUMORIGENESIS AND CHROMOSOMAL INSTABILITY/

We have examined defects in mammary development and tumorigenesis in a transgenic model expressing the c-myc gene under the MMTV-LTR promote r, The stochastic tumors which arise from hyperplastic ductal and lobu lar lesions in this model are characterized by high rates both of apop tosis and of chromosomal instability, Since the p53 gene product is th ought to be central in the maintenance of genomic integrity, in part d ue to its ability to induce apoptosis in cells harboring DNA damage, w e examined its expression and possible mutation. Initially, we observe d that unmutated p53 is strongly expressed in premalignant mammary gla nds and in mammary tumors derived from the MMTV-c-myc strain. We then mated the MMTV-myc strain to a p53-deficient strain as a means of exam ining the effect of this lesion on mammary development and tumorigenes is in the context of c-myc overexpression, A lack of both p53 alleles in the presence of c-myc overexpression resulted in a dramatic hyerpla stic alteration in mammary gland development, Specifically, in female bitransgenic MMTV-c-myc/p53 null mice (MMTV-myc/p53(-/-)), lobular hyp erplasias were observed at almost every ductal end bud as early as 32 days of age, In contrast, only mild ductal and lobular hyperplasias we re seen in MMTV-myc mice that contained both p53 alleles (MMTV-myc/p53 (+/+)); an intermediate phenotype occurred in mice with a single intac t (MMTV-myc/p53(+/-)) p53 allele, Mammary carcinomas arose with a high frequency in MMTV-myc/p53(+/-) mice; the tumors were comparable in fr equency, histology and apoptotic index to the tumors in MMTV-myc/p53(/+) mice, Also, as previously observed (Elson et al,, 1995), lymphomas arose with extremely short latency in MMTV-myc/ p53(-/-) mice, preclu ding study of the fate of their hyperplastic mammary lesions in situ, The frequency of p53 mutations in MMTV-myc/p53(+/+) and MMTV-myc/ p53/- mammary tumors and in cell lines derived from these tumors was exam ined by direct sequencing. No point mutations or deletions in p53 were observed in mammary tumors or cell lines from either genotype, Finall y, a detailed chromosomal analysis using multicolor spectral karyotypi ng (SKY) revealed that there were multiple chromosomal alterations in the c-myc-overexpressing cells that contained either one or two unmuta ted p53 alleles, Variable ploidy changes, a common translocation of ch romosome 11, and other chromosomal aberrations were observed. Our data thus support an interaction between c-Myc and p53 in mammary developm ent, but suggest that loss of p53 is required neither for c-myc-depend ent tumorigenesis nor for c-myc-dependent chromosomal instability.