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Epidemiology and Prevention |
Departments of 1 Cell and Developmental Biology and 2 Medicine, Weill Medical College of Cornell University; 3 Strang Cancer Research Laboratory, Rockefeller University; Departments of 4 Epidemiology and Biostatistics and 5 Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 6 Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut; 7 Department of Biochemistry, McGill University, Montreal, Quebec, Canada; 8 Center for Comparative Medicine, University of California, Davis, California; and 9 Pharmaceutical Development Center, M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Louise R. Howe, Strang Cancer Research Laboratory, Rockefeller University, Box 231, 1230 York Avenue, New York, NY 10021. Phone: 212-734-0567; Fax: 212-472-9471; E-mail: lrhowe{at}med.cornell.edu.
The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in 
40% of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasias, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs.
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