HER-2/neu status is a determinant of mammary aromatase activity in vivo: Evidence for a cyclooxygenase-2-dependent mechanism Journal Article
| Authors: | Subbaramaiah, K.; Howe, L. R.; Port, E. R.; Brogi, E.; Fishman, J.; Liu, C. H.; Hla, T.; Hudis, C.; Dannenberg, A. J. |
| Article Title: | HER-2/neu status is a determinant of mammary aromatase activity in vivo: Evidence for a cyclooxygenase-2-dependent mechanism |
| 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. ©2006 American Association for Cancer Research. |
| Keywords: | protein expression; human cell; nonhuman; mouse; animals; mice; enzyme inhibition; breast cancer; epidermal growth factor receptor 2; animal experiment; in vivo study; in vitro study; enzyme activity; mice, transgenic; celecoxib; cyclooxygenase 2 inhibitors; pyrazoles; sulfonamides; cyclooxygenase 2; prostaglandin e2; receptor, erbb-2; aromatase inhibitors; mammary glands, animal; nih 3t3 cells; aromatase; dinoprostone |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 10 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-05-15 |
| Start Page: | 5504 |
| End Page: | 5511 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-05-4076 |
| PUBMED: | 16707480 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 48" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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