HER-2/neu status is a determinant of mammary aromatase activity in vivo: Evidence for a cyclooxygenase-2-dependent mechanism

Kotha Subbaramaiah, Louise R. Howe, Elisa R. Port, Edi Brogi, Jack Fishman, Catherine H. Liu, Timothy Hla, Clifford Hudis, Andrew J. Dannenberg

Research output: Contribution to journalArticle

80 Scopus citations

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 E2 (PGE2) levels were increased in mice with mammary-targeted expression of a COX-2 transgene. In vitro, overexpressing COX-2 caused both increased PGE2 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 PGE2 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 PGE2 synthesis will suppress estrogen biosynthesis in breast tissue.

Original languageEnglish (US)
Pages (from-to)5504-5511
Number of pages8
JournalCancer research
Volume66
Issue number10
DOIs
StatePublished - May 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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