To ascertain differences between solely
hormone- and chemical
carcinogen-induced murine mammary gland
tumors (MGTs), a direct comparison of their ploidy status was assessed. Nuclear image cytometry (NIC) was used to evaluate ploidy in
ductal carcinoma in situ (
DCIS) and MGTs induced solely by 17beta-estradiol (E(2)) in female A-strain Copenhagen Irish hooded gene rats (ACI) and E(2) plus
testosterone propionate in male Noble rats. These results were compared to ploidy data from primary MGTs induced by two synthetic
carcinogens, 7,12-dimethylbenz[a]antracene and
nitrosomethylurea in female Brown Lewis Norway rats and an environmental
carcinogen,
6-nitrochrysene, in female Sprague-Dawley rats. Both
DCIS and primary MGTs induced solely by
hormones were highly
aneuploid (> 84%), whereas MGTs induced by either synthetic or
environmental carcinogens were primarily diploid (> 85%). Examination of 76 metaphase plates obtained from eight individual E(2)-induced ACI female rat MGTs revealed the following consistent chromosome alterations: gains in chromosomes 7, 11, 12, 13, 19, and 20 and loss of chromosome 12. On Southern blot analysis, six of nine ACI female rat primary E(2)-induced MGTs (66%) exhibited amplified copy numbers (range: 3.4-6.9 copies) of the c-myc gene. Fluorescence in situ hybridization (FISH) analysis of these MGTs revealed specific fluorescent hybridization signals for c-myc (7q33) on all three homologs of a
trisomy in chromosome 7. NIC analysis of 140 successive nonfamilial sporadic invasive human ductal breast
cancers (BCs) showed an
aneuploid frequency of 61%, while 31 DCISs revealed a 71%
aneuploid frequency. These results clearly demonstrate that the female ACI rat E(2)-induced MGTs more closely resemble invasive human
DCIS and ductal BC in two pertinent aspects: they are highly
aneuploid compared with chemical
carcinogen-induced MGTs and exhibit a high frequency of c-myc amplification.