Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer. Several molecular alterations have been identified in DCIS. Among them, cyclooxygenase 2 (COX-2) overexpression has been shown in 60% to 80% of DCIS cases. Celecoxib is a nonsteroidal anti-inflammatory drug that selectively inhibits COX-2. In this study, we evaluated whether COX-2 inhibition by celecoxib can reduce the incidence of preinvasive breast cancer and its progression to invasive breast cancer in a mouse model exhibiting a similar phenotype to human solid-pattern DCIS. We have used the mouse model mouse mammary tumor virus (MMTV)-Neu to investigate this possibility. These mice carry a rat Her-2/Neu transgene and are known to develop DCIS-like lesions. Our results showed that celecoxib (500 ppm) given as prophylaxis was neither able to prevent tumor development nor delay tumor appearance compared with untreated mice. Furthermore, when the drug was given early in tumorigenesis, it did not reduce the progression of preinvasive to invasive tumors nor prevent lung metastasis. Reduction of prostaglandin levels was, however, achieved in mammary tumors of treated mice. In addition, celecoxib treatment caused an increase in apoptosis and decreased vascular endothelial growth factor expression in treated animals. Our results contrast with some previously published studies and highlight the complexity of the relationship between COX-2 and breast cancer. Cancer Prev Res; 3(2); 202-11. ©2010 AACR.