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Lani · 08-23-2006, 02:14 AM

[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)

08-23-2006, 02:14 AM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	could a cox2 inhibitor replace antihormonals in her2neu+ breast cancer therapy? [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)