title: Aurora a and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia.
abstract: Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92-94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor alpha. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis.
authors.affiliation: Hormonal Carcinogenesis Laboratory, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Adrianne E
authors.initials: AE
authors.lastname: Hontz
authors.forename: Sara Antonia
authors.initials: SA
authors.lastname: Li
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Lingle
authors.forename: Vivian
authors.initials: V
authors.lastname: Negron
authors.forename: Amy
authors.initials: A
authors.lastname: Bruzek
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Salisbury
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000782:Aneuploidy; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D064127:Aurora Kinases; D015153:Blotting, Western; D018385:Centrosome / Q000201:enzymology*; D043171:Chromosomal Instability; D006224:Cricetinae; D004958:Estradiol; D007668:Kidney / Q000187:drug effects; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008647:Mesocricetus; D009919:Orchiectomy; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D013629:Tamoxifen; D004958:Estradiol; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases