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Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August͞Copenhagen͞Irish) rats treated with essentially physiological serum levels of 17␤-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, ␥-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5-6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5-6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55-82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor ␣ to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells. More than 90% of all human breast cancer (BC) cases are sporadic (1). Numerous epidemiological and animal studies show that both endogenous and exogenously ingested estrogens (Es) play a central, if not paramount, role in the causation and development of human sporadic BC (2-6). Recent epidemiological studies show only a minimal rise in BC risk in postmenopausal women taking E replacement therapy over varying periods of use (7-9). In premenopausal women, however, all of the well established risk factors clearly implicate Es in the causation of BC (2-6). In this latter group, 17␤-estradiol (E 2 ) concentrations, all in the low picogram range, within narrow limits of serum and breast tissue levels (10-13), are sufficient to increase sporadic BC risk. Therefore, it is essential to gain a better understanding of how Es, at these physiological concentrations, elicit their oncogenic effects in susceptible target tissues.Chromosomal instability (CIN) and aneuploidy are defining traits of early human BC ductal carcinoma in situ (DCIS) and primary invasive ductal BCs. These distinguishing characteristics of human BC have been seen in 55-78% of the DCISs and in 85-92% of invasive ductal BCs (14-17). Aneuploidy has been a reliable biomarker for BC for many decades. However, it has not been realized until now that it provides an important clue to the causation of sporadic human BC and the involvement of Es in its etiology.Overexpression of a centrosome kinase, Aurora-A (Aur-A), centrosome amplification, and CIN invariably occur together (18,19). Centrosome amplification, found in human BC, may play...

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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.