Subbaramaiah Kotha, Howe Louise R, Port Elisa R, Brogi Edi, Fishman Jack, Liu Catherine H, Hla Timothy, Hudis Clifford, Dannenberg Andrew J
Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA.
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.
细胞色素P450芳香化酶（芳香化酶）是CYP19基因的产物，可催化雄激素合成雌激素。鉴于雌激素合成在激素依赖性乳腺癌发生中的重要性，阐明调节CYP19表达的机制非常重要。本研究的主要目的是确定乳腺组织中HER-2/neu、环氧化酶-2（COX-2）和芳香化酶之间的相互关系。在乳腺靶向表达COX-2转基因的小鼠中，乳腺芳香化酶活性和前列腺素E2（PGE2）水平升高。在体外，过表达COX-2导致PGE2生成增加和芳香化酶活性增强，这些作用被选择性COX-2抑制剂塞来昔布抑制。此前，我们发现HER-2/neu的过表达与人乳腺癌中COX-2水平升高有关。在此，我们表明HER-2/neu的过表达也与芳香化酶活性增加有关。这些结果提示COX-2可能是连接HER-2/neu和芳香化酶的功能中间体。与此观点一致，在HER-2/neu转基因小鼠模型中，COX-2缺陷导致乳腺芳香化酶活性呈基因剂量依赖性降低。补充的体外研究表明，抑制COX-2可抑制HER-2/neu介导的PGE2合成诱导和芳香化酶活性。总体而言，我们的数据表明COX-2是连接HER-2/neu和芳香化酶的功能中间体，并提示PGE2合成抑制剂将抑制乳腺组织中的雌激素生物合成。
