Nonrandom abnormalities involving chromosome 1 and Harvey-ras-1 alleles in rat mammary tumor progression

Abstract

Little is known about the role of chromosomal abnormalities in the widely used models of rat mammary carcinogenesis. In this study, we cytogenetically analyzed nitrosomethylurea-induced rat mammary adenocarcinomas at different time points of development. As tools to study more advanced stages of malignant progression, we also analyzed the cytogenetic progression of tumors transplanted into younger syngeneic hosts, and of tumors that did not regress or that developed after host ovariectomy. Our results indicate that rat mammary adenocarcinomas appear to start development as diploid lesions with cytogenetically "normal" karyotypes. However, upon progression, tumors showed coexistence of normal diploid clones with abnormal clones bearing specific abnormalities affecting mainly chromosomes 1 and 15. Almost every ovary-independent tumor presented stem lines with specific nonrandom chromosomal abnormalities. Numerical chromosomal abnormalities such as specific trisomies started to develop mainly after subsequent in vivo transplantations. The abnormalities affecting chromosome 1 observed in many tumors were: (a) interstitial deletions and breakpoints for translocation in region 1q22; and (b) partial or complete overrepresentation of chromosome 1 in the form of direct duplication of region 1q22q43 or as trisomy 1. Interestingly, Harvey-ras-1 gene maps to rat chromosome 1, and by Southern analysis we observed that 4 of 8 primary tumors and 6 of 9 ovary-independent tumors showed considerable loss of Harvey-ras-1 signal indicating probable allele loss. However, analyses of some tumor transplants in more advanced stages of progression showed, paradoxically, an increased copy number of the Harvey-ras-1 oncogene coinciding with the presence of the direct duplication observed in chromosome 1 or with trisomy 1 as possible mechanisms for gene amplification. Interestingly, rat chromosome 1 is the homologue to human chromosome 11, and in numerous cases of human breast cancer loss of heterozygosity of several genes in chromosome 11p15.5 has been reported. Some of the rat chromosome 1 abnormalities observed may be equivalent to those affecting 11p15 in human tumors. We also observed 8 tumors with abnormalities affecting chromosome 15. At least 3 genes of interest in breast cancer have been previously mapped to that rat chromosome. The similarities observed with human breast cancer may point to common mechanisms of tumor progression in both species.