COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer

• Published in: BMC cancer Vol. 10; no. 1; p. 626
• Main Authors: Glynn, Sharon A, Prueitt, Robyn L, Ridnour, Lisa A, Boersma, Brenda J, Dorsey, Tiffany M, Wink, David A, Goodman, Julie E, Yfantis, Harris G, Lee, Dong H, Ambs, Stefan
• Format: Journal Article
• Language: English
• Published: England BioMed Central 15.11.2010; BioMed Central Ltd; BMC
• Subjects: Adult; Aged; bcl-Associated Death Protein - biosynthesis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Caspase 9 - biosynthesis; Cyclooxygenase 2 - biosynthesis; Estrogen Receptor alpha - biosynthesis; Female; Gene Expression Regulation, Neoplastic; Genes, p53; Hospitals; Humans; Immunohistochemistry - methods; Medical research; Middle Aged; Pathology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Receptor, ErbB-2 - biosynthesis; Treatment Outcome; Tumors
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-10-626

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. 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. 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. 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.