title: Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2.
abstract: OBJECTIVE
  Aurora kinase A (Aurora-A) is known to regulate genomic instability and tumorigenesis in multiple human cancers. The underlying mechanism, however, is not fully understood. We examined the molecular mechanism of Aurora-A regulation in human ovarian cancer.
  
  
  METHODS
  Retrovirus-mediated small hairpin RNA (shRNA) was used to silence the expression of Aurora-A in the ovarian cancer cell lines SKOV3, OVCA432, and OVCA433. Immunofluorescence, Western blotting, flow cytometry, cytogenetic analysis, and animal assay were used to test centrosome amplification, cell cycle alteration, apoptosis, DNA damage response, tumor growth, and genomic instability. Immunostaining of BRCA2 and Aurora-A was done in ovarian, pancreatic, breast, and colon cancer samples.
  
  
  RESULTS
  Knockdown of Aurora-A reduced centrosome amplification, malformation of mitotic spindles, and chromosome aberration, leading to decreased tumor growth. Silencing Aurora-A attenuated cell cycle progression and enhanced apoptosis and DNA damage response by restoring p21, pRb, and BRCA2 expression. Aurora-A was inversely correlated with BRCA2 in high-grade ovarian serous carcinoma, breast cancer, and pancreatic cancer. In high-grade ovarian serous carcinoma, positive expression of BRCA2 predicted increased overall and disease-free survival, whereas positive expression of Aurora-A predicted poor overall and disease-free survival (P < 0.05). Moreover, an increased Aurora-A to BRCA2 expression ratio predicted poor overall survival (P = 0.047) compared with a decreased Aurora-A to BRCA2 expression ratio.
  
  
  CONCLUSIONS
  Aurora-A regulates genomic instability and tumorigenesis through cell cycle dysregulation and BRCA2 suppression. The negative correlation between Aurora-A and BRCA2 exists in multiple cancers, whereas the expression ratio of Aurora-A to BRCA2 predicts ovarian cancer patient outcome.
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gong
authors.initials: G
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Chang
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guo
authors.forename: Kathy Qi
authors.initials: KQ
authors.lastname: Cai
authors.forename: Xue Sherry
authors.initials: XS
authors.lastname: Xiao
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.forename: Imelda
authors.initials: I
authors.lastname: Mercado-Uribe
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
mesh_terms: D017209:Apoptosis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D005260:Female; D020868:Gene Silencing; D042822:Genomic Instability; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D024682:BRCA2 Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases