Loss of chromosomal integrity drives rat mammary tumorigenesis.
Breast cancer incidence varies with diet and other environmental influences, including carcinogen exposure. However, the effects of carcinogens on cell growth control pathways are poorly understood. Here, we have examined processes that are activated in the mammary glands of rats treated with 1-methyl-1-nitrosourea (MNU). This synthetic carcinogen was used to study events occurring during mammary tumor initiation and development. In female Wistar-Furth rats, given 1 dose of MNU beginning at 50 days of age, 84% of the rats developed tumors by 46 weeks of age (latency 13-15 weeks). Changes in the gland occurred as early as 1-day post-MNU. Cells exhibited DNA damage, leading to chromosomal instability, supernumerary centrosomes and higher levels of Aurora A; these events correlated with the appearance of preneoplasia in the glands. In mammary tumors, elevated numbers of centrosomes coincided with genomic instability. Tumors were transplanted into syngeneic hosts and subsequent tumor generations displayed the same marker chromosomes in mostly aneuploid metaphases with hyperdiploid numbers of chromosomes, suggesting that clonality and aneuploidy were passed on from one generation to the next. Collectively, these data suggest that the carcinogen MNU induces changes resulting in genetic instability detectable before hyperplasia and tumors develop in the rat mammary gland.
Goepfert
Thea M
TM
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. goepfert@bcm.tmc.edu
Moreno-Smith
Myrthala
M
Edwards
David G
DG
Pathak
Sen
S
Medina
Daniel
D
Brinkley
W R
WR
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D018385:Centrosome / Q000201:enzymology / Q000473:pathology; D043171:Chromosomal Instability; D005260:Female; D007621:Karyotyping; D008321:Mammary Glands, Animal / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D008770:Methylnitrosourea / Q000633:toxicity; D009368:Neoplasm Transplantation; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D051381:Rats; D011920:Rats, Inbred WF
D000951:Antigens, Neoplasm; D008770:Methylnitrosourea; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases