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.