ALLELOTYPIC AND CYTOGENETIC CHARACTERIZATION OF CHEMICALLY-INDUCED MOUSE MAMMARY-TUMORS - HIGH-FREQUENCY OF CHROMOSOME-4 LOSS OF HETEROZYGOSITY AT ADVANCED STAGES OF PROGRESSION

Loss of heterozygosity (LOH) is one of the most common genetic abnorma lities in cancer. To define the role of LOH and chromosomal abnormalit ies at various stages of mouse mammary cancer progression, we analyzed the allelotypes and karyotypes of primary mammary tumors induced in C D2F(1) mice by two basic protocols, the classical multiple-dose 7,12-d imethylbenz[a]anthracene (DMBA) protocol and a novel protocol of combi ned medroxyprogesterone acetate (MPA) and DMBA. The advantage of the l atter protocol is that its latency for tumor development is much short er and its tumor incidence is higher than those of DMBA alone. To stud y more advanced stages of mammary tumor progression, we also analyzed mouse mammary tumors that had acquired autonomous growth and were tran splantable into syngeneic hosts. The allelotypic studies were performe d by means of microsatellite length polymorphism analysis with a minim um of two simple-sequence repeat markers per chromosome. We observed t hat MPA-DMBA-induced mammary adenocarcinomas, which in general arose e arlier because of the growth promotion exerted by MPA, did not show an y significant LOH and were essentially diploid. Tumors induced by DMBA alone, which on average took longer to develop, showed a higher frequ ency of allelic losses. LOH on chromosome 11 was observed in 30% of th e cases. Chromosomes 4 and 8 were affected in 25% and 20% of the tumor s, respectively. Interestingly, advanced stages of mammary tumor progr ession, represented by transplantable mammary tumors, showed a much hi gher 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 tran splantation ability, (C) 1996 Wiley-Liss, Inc.