title: COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer.
abstract: BACKGROUND
  Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation.
  
  
  METHODS
  Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival.
  
  
  RESULTS
  COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196.
  
  
  CONCLUSIONS
  Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland (MD), USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Glynn
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Prueitt
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Boersma
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Dorsey
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Julie E
authors.initials: JE
authors.lastname: Goodman
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.forename: Stefan
authors.initials: S
authors.lastname: Ambs
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D053453:Caspase 9 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D016896:Treatment Outcome; D051025:bcl-Associated Death Protein / Q000096:biosynthesis
chemical_list: D053453:Caspase 9; D051546:Cyclooxygenase 2; D047628:Estrogen Receptor alpha; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D051025:bcl-Associated Death Protein; C494819:BAD protein, human