Allelotypic and cytogenetic characterization of chemically induced mouse mammary tumors: High frequency of chromosome 4 loss of heterozygosity at advanced stages of progression

Abstract

Loss of heterozygosity (LOH) is one of the most common genetic abnormalities in cancer. To define the role of LOH and chromosomal abnormalities at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in CD2F, mice by two basic protocols, the classical multiple-dose 7,12-dimethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combined medroxyprogesterone acetate (MPA) and DMBA. The advantage of the latter protocol is that its latency for tumor development is much shorter and its tumor incidence is higher than those of DMBA alone. To study more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were transplantable into syngeneic hosts. The allelotypic studies were performed by means of microsatellite length polymorphism analysis with a minimum of two simple-sequence repeat markers per chromosome. We observed that MPA-DMBA-induced mammary adenocarcinomas, which in general arose earlier because of the growth promotion exerted by MPA, did not show any significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequency of allelic losses. LOH on chromosome 11 was observed in 30% of the cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumors, respectively. Interestingly, advanced stages of mammary tumor progression, represented by transplantable mammary tumors, showed a much higher level of genomic instability, specifically a very high frequency (66%) of LOH on chromosome 4. These findings indicate that chromosome 4 harbors a gene whose inactivation may play a role in the acquisition of more aggressive characteristics such as autonomous growth and transplantation ability.

A comparative analysis of allelic imbalance events in chemically induced rat mammary, colon, and bladder tumors

“…Rat chromosome 5 shows high homology to mouse chromosome 4 [21,23]. As previously stated, genetic alterations of mouse chromosome 4 are found in a variety of mouse tumors [1][2][3][4][5]. The rat genetic marker D5Mit4, which showed AI in our study, is located within 10 cM of the tyrosine phosphatase 1 gene.…”

Loss of chromosomal integrity drives rat mammary tumorigenesis

“…Published data reported that these primary tumors are thought to exhibit a low frequency of LOH (loss of heterozygocity) and no apparent genetic instability. 31,32 Because of the inconsistency of our results to published data it was necessary to further investigate the ploidy and chromosome composition of these tumor samples.…”

“…Centrosome anomalies and Aurora A overexpression can coincide with errors occurring during cell cycle and cell division, and are therefore a good indicator for genomic instability and aneuploidy. Published data reported that these primary tumors are thought to exhibit a low frequency of LOH (loss of heterozygocity) and no apparent genetic instability 31, 32. Because of the inconsistency of our results to published data it was necessary to further investigate the ploidy and chromosome composition of these tumor samples.…”

Identification of Metastasis-Related Proteins and Their Clinical Relevance to Triple-Negative Human Breast Cancer

“…Most of the tumors were lobular in morphology and progressively ceased to express receptors after a few in vivo passages. In mice, progestins can act as cocarcinogens together with chemical initiators, such as N-methyl-N-nitrosourea (35) and dimethylbenzanthracene (36). Recent studies in PR knockout mice confirmed the role of PR on dimethylbenzanthracene-induced tumorigenesis (37).…”