Back to Search
Start Over
HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism.
- Source :
-
Cancer research [Cancer Res] 2006 May 15; Vol. 66 (10), pp. 5504-11. - Publication Year :
- 2006
-
Abstract
- Cytochrome P450 aromatase (aromatase), a product of the CYP19 gene, catalyzes the synthesis of estrogens from androgens. Given the significance of estrogen synthesis in hormone-dependent breast carcinogenesis, it is important to elucidate the mechanisms that regulate CYP19 expression. The main objective of this study was to define the interrelationship between HER-2/neu, cyclooxygenase-2 (COX-2), and aromatase in mammary tissue. Mammary aromatase activity and prostaglandin E(2) (PGE(2)) levels were increased in mice with mammary-targeted expression of a COX-2 transgene. In vitro, overexpressing COX-2 caused both increased PGE(2) production and aromatase activity, effects that were suppressed by celecoxib, a selective COX-2 inhibitor. Previously, we found that overexpression of HER-2/neu was associated with increased levels of COX-2 in human breast cancers. Here, we show that overexpression of HER-2/neu is also associated with increased aromatase activity. These results suggested the possibility that COX-2 was the functional intermediate linking HER-2/neu and aromatase. Consistent with this idea, COX-2 deficiency led to a gene dose-dependent reduction in mammary aromatase activity in a HER-2/neu transgenic mouse model. Complementary in vitro studies showed that HER-2/neu-mediated induction of PGE(2) synthesis and aromatase activity were suppressed by inhibiting COX-2. Collectively, our data indicate that COX-2 is the functional intermediate linking HER-2/neu and aromatase and suggest that inhibitors of PGE(2) synthesis will suppress estrogen biosynthesis in breast tissue.
- Subjects :
- Animals
Aromatase Inhibitors pharmacology
Celecoxib
Cyclooxygenase 2 biosynthesis
Cyclooxygenase 2 genetics
Cyclooxygenase 2 Inhibitors pharmacology
Dinoprostone biosynthesis
Dinoprostone metabolism
Humans
Mammary Glands, Animal enzymology
Mice
Mice, Transgenic
NIH 3T3 Cells
Pyrazoles pharmacology
Receptor, ErbB-2 biosynthesis
Receptor, ErbB-2 deficiency
Receptor, ErbB-2 genetics
Sulfonamides pharmacology
Aromatase metabolism
Cyclooxygenase 2 metabolism
Mammary Glands, Animal metabolism
Receptor, ErbB-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16707480
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-05-4076