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

Cancer Res. 2006 May 15;66(10):5504-11. doi: 10.1158/0008-5472.CAN-05-4076.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aromatase / metabolism*
  • Aromatase Inhibitors / pharmacology
  • Celecoxib
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Dinoprostone / biosynthesis
  • Dinoprostone / metabolism
  • Humans
  • Mammary Glands, Animal / enzymology
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • NIH 3T3 Cells
  • Pyrazoles / pharmacology
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / deficiency
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Sulfonamides / pharmacology


  • Aromatase Inhibitors
  • Cyclooxygenase 2 Inhibitors
  • Pyrazoles
  • Sulfonamides
  • Aromatase
  • Cyclooxygenase 2
  • Receptor, ErbB-2
  • Celecoxib
  • Dinoprostone