Carcinogenesis, Vol 19, 223-227, Copyright © 1998 by Oxford University Press
J Lu, C Jiang, T Mitrenga, G Cutter and HJ Thompson
The induction of mammary carcinogenesis in the rat by 1-methyl-1-
nitrosourea (MNU) is widely used in experimental breast cancer research. In
the experiments reported, the Ha-ras codon 12 (ras12) mutation
(GGA-->GAA) was used as a molecular marker to address issues of the
clonality of carcinomas induced, pathogenetic independence among multiple
carcinomas within the same animal and topographic distribution of mutant
ras12 carcinomas in different mammary gland chains. In order to determine
whether the frequently observed morphologically distinguishable lobules
within carcinomas originate from the coalescence of independent lesions or
whether cancerous cells within a carcinoma share a common origin, 44
randomly selected MNU-induced mammary carcinomas were genotyped for two to
four lobules each for the ras12 mutation. A total of 43 carcinomas out of
44 (97.7%) had concordant ras12 genotypes among the multiple sites within
each tumor, which is consistent with the latter possibility. Next, it was
observed that as carcinoma multiplicity increased, the discordance rate of
ras12 genotypes among multiple carcinomas within the same animal increased
in a manner that was in excellent agreement with the expected discordance
rate based on an assumption of no pathogenetic association among
carcinomas. Furthermore, a significant difference was observed in the
occurrence of mutant ras12 carcinomas between the cervical-thoracic and the
abdominal-inguinal mammary glands in that three times as many carcinomas
were mutant in the former as in the latter glands, whereas the occurrence
of wild-type carcinomas was approximately the same in both regions. Taken
together, the data are consistent with (i) carcinomas induced by MNU and
detected by palpation are monoclonal in origin, (ii)
independently-initiated cells emerge as distinct mammary carcinomas in the
same animal, and (iii) the anatomical location of the gland may affect the
prevalence of mammary carcinomas that harbor a mutant ras12.
ARTICLES
Pathogenic characterization of 1-methyl-1-nitrosourea-induced mammary carcinomas in the rat
Center for Cancer Causation and Prevention, AMC Cancer Research Center, Denver, CO 80214, USA. luj@amc.org
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