Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats.
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 (August/Copenhagen/Irish) rats treated with essentially physiological serum levels of 17beta-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, gamma-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 alpha to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells.
Li
Jonathan J
JJ
Hormonal Carcinogenesis Laboratory, Department of Pharmacology, Toxicology, and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA. jli1@kumc.edu
Weroha
S John
SJ
Lingle
Wilma L
WL
Papa
Dan
D
Salisbury
Jeffrey L
JL
Li
Sara Antonia
SA
D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018385:Centrosome / Q000648:ultrastructure*; D002875:Chromosomes / Q000648:ultrastructure*; D004247:DNA / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D047468:Immunoprecipitation; D008321:Mammary Glands, Animal / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D011494:Protein Kinases / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D029867:Xenopus Proteins
D018797:Cell Cycle Proteins; D004967:Estrogens; D012333:RNA, Messenger; D029867:Xenopus Proteins; D004247:DNA; D011494:Protein Kinases; C112134:AURKA protein, Xenopus; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases