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Open Access Highly Accessed Research article

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

Sharon A Glynn12, Robyn L Prueitt1, Lisa A Ridnour3, Brenda J Boersma1, Tiffany M Dorsey1, David A Wink3, Julie E Goodman4, Harris G Yfantis5, Dong H Lee5 and Stefan Ambs1*

Author Affiliations

1 Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland (MD), USA

2 Cancer Prevention Fellowship Program, Office of Preventive Oncology, NCI, NIH, Bethesda, MD, USA

3 Radiation Biology Branch, CCR, NCI, NIH, Bethesda, MD, USA

4 Gradient Corporation, Cambridge, Massachusetts, USA

5 Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, MD, USA

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BMC Cancer 2010, 10:626  doi:10.1186/1471-2407-10-626

Published: 15 November 2010

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.