could a cox2 inhibitor replace antihormonals in her2neu+ breast cancer therapy?

[Lani]

[Cancer Research 66, 5504-5511, May 15, 2006]
© 2006 American Association for Cancer Research
Epidemiology and Prevention

HER-2/neu Status Is a Determinant of Mammary Aromatase Activity In vivo: Evidence for a Cyclooxygenase-2-Dependent Mechanism

Kotha Subbaramaiah1, Louise R. Howe2,3, Elisa R. Port4, Edi Brogi5, Jack Fishman1, Catherine H. Liu7, Timothy Hla7, Clifford Hudis6 and Andrew J. Dannenberg1
Departments of 1 Medicine and 2 Cell and Developmental Biology, Weill Medical College of Cornell University; 3 Strang Cancer Research Laboratory at The Rockefeller University; Departments of 4 Surgery, 5 Pathology, and 6 Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and 7 Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut

Requests for reprints: Kotha Subbaramaiah, New York Presbyterian Hospital-Cornell, 525 East 68th Street, Room F-203A, New York, NY 10021. Phone: 212-746-4402; Fax: 212-746-4885; E-mail: ksubba@med.cornell.edu or Andrew J. Dannenberg, New York Presbyterian Hospital-Cornell, 525 East 68th Street, Room F-206, New York, NY 10021. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen@med.cornell.edu.

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. (Cancer Res 2006; 66(10): 5504-11)

[RobinP]

Lani thanks for the post; interesting article. What do you think about taking tumeric as a cox inhibitor? Do you think it has any of the same cardiac toxicities as something like celebrex.

[Lani]

There is no money to be made, research required or safety to be proved with tumeric, so little research will probably be done regarding its effects in a dose related fashion(some compounds have opposite effects when given in higher or lesser doses), in different age groups, in people with different ways to metabolize the compounds, or in combination with different medications, in those with compromised liver or kidney function, etc.

Lots of work has been done on NSAIDS especially those that have been on the market for over 25 years (clinoril, naprosyn, ibuprofen, etc) Naprosyn seems to be the one they are now using as the one to compare against with respect to safety (ie, the one considered the safest) in my review of the recent literature.

Remember there are two other enzymes besides aromatase (actually more because they have subsets of enzymes) involved in the local production of estradiol or estrone in the breast cancer cells or their immediate local microenvironment.

There is a lot still to work out here...

[Lani]

plus other food may contain compounds which bind up the active ingredient in tumeric, or inhibit or potentiate it. Lots of unknown variables!

[Lani]

a sulfatase!:
1: J Steroid Biochem Mol Biol. 2006 Aug 21; [Epub ahead of print] Links
Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer An immunocytochemical study.

Song D,
Liu G,
Luu-The V,
Zhao D,
Wang L,
Zhang H,
Xueling G,
Li S,
Desy L,
Labrie F,
Pelletier G.
First Teaching Hospital of Jilin University, ChangChun, China.
It is known that there is a local biosynthesis of estradiol (E2) in breast carcinoma. The steroidogenic enzymes involved in E2 formation are aromatase which transforms testosterone into E2 and androstenedione into estrone (E1) and reductive 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) which convert E1 into E2. Using immunocytochemistry, we have studied the expression of aromatase and the three reductive 17beta-HSDs 17beta-HSD types 1, 7 and 12 in 41 specimens of female human breast carcinoma and adjacent non-malignant tissues. These results were correlated with the estrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor, androgen receptor, CDC47 and c-erb B-2 expressions and with the tumor stages. Aromatase was found in 58%, 17beta-HSD type 7 in 47% and 17beta-HSD type 12 in 83% of the breast cancer specimens. The 17beta-HSD type 1 could be detected in only one tumor. A significant correlation was observed between the aromatase, 17beta-HSD type 7 and 17beta-HSD type 12 expression, as well as between each of the two enzymes 17beta-types 7 and 12 and the ERbeta expression. The expression of 17beta-HSD type 12 was significantly higher in breast carcinoma specimens than in normal tissue. There was also a significant association of CDC 47 expression with ERbeta, AR and 17beta-HSD type 12. The results indicate that aromatase, 17beta-HSD type 7 and 17beta-HSD type 12, but not 17beta-HSD type 1, are commonly expressed in human breast cancer. Moreover, the high expression of both 17beta-HSD type 12 and ERbeta in breast carcinoma cells may play a role in the development and/or progression of breast cancer.
PMID: 16930994 [PubMed - as supplied by publisher]