Distinct pattern of allelic loss and inactivation of cadherin 1 and 5 genes in mammary carcinomas arising in p53(+/-) mice.
p53 is one of the most frequently mutated genes in mammary carcinomas (MCs). To detect tumor suppressor genes cooperating with a hetero-deficient p53 gene in mammary carcinogenesis, we first examined allelotypes in MCs from (BALB/cHeA x MSM/Ms) F(1)- p53(+/-) and (BALB/cHeA x 129/SvEv) F(1)- p53(+/-) female mice, and then surveyed down-regulated genes in the allelic loss regions. Genome-wide screening at 42 loci identified frequent (more than 30%) loss of heterozygosity (LOH) on chromosomes 5, 8, 11, 12, 14 and 18 in the MCs from either of the F(1) mice. The MCs in the p53(+/- )mice indicated highly frequent LOH, especially on chromosomes 8, 11 and 12, distinct from other mouse tumors. More than 60% of the 38 MCs from (BALB/cHeA x MSM/Ms) F(1)- p53 (+/-) mice showed LOH in a region ranging from D8Mit85 (105.0 Mb from centromere) to D8Mit113 (111.8 Mb) on chromosome 8, a region syntenic to human chromosome 16q22.1, on which LOH has been found in breast cancers. RT-PCR analyses revealed that the LOH of chromosome 8 was associated with the reduced and/or complete loss of expression of Cdh1 and Cdh5 genes in 15 (58%) and 8 (31%) of 26 MCs derived from the F(1) mice, respectively. Thus, inactivation of Cdh1 and Cdh5 is likely to cooperate with the loss of p53, suggesting a possible tumor suppressive function of these genes in mammary carcinogenesis.
Umesako
Seiichi
S
Graduate School of Agriculture and Biological Sciences, Osaka Prefecture University, Sakai, Japan.
Iiga
Sayoko
S
Takahashi
Masahiro
M
Imura
Kae
K
Mori
Nobuko
N
Hong
Doo-Pyo
DP
Song
Chang-Woo
CW
Niwa
Otsura
O
Okumoto
Masaaki
M
D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018895:Microsatellite Repeats; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000099152:Cadherin 5