HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice.
The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in approximately 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.
Howe
Louise R
LR
Department of Cell and Developmental Biology, Weill Medical College of Cornell University, NY, USA. lrhowe@med.cornell.edu
Chang
Sung-Hee
SH
Tolle
Kelly C
KC
Dillon
Rachelle
R
Young
Lawrence J T
LJ
Cardiff
Robert D
RD
Newman
Robert A
RA
Yang
Peiying
P
Thaler
Howard T
HT
Muller
William J
WJ
Hudis
Clifford
C
Brown
Anthony M C
AM
Hla
Timothy
T
Subbaramaiah
Kotha
K
Dannenberg
Andrew J
AJ
D000818:Animals; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
D051546:Cyclooxygenase 2; D018719:Erb-b2 Receptor Tyrosine Kinases