Title

Functional role of cyclooxygenase-2 in mammary gland tumorangiogenesis

Date of Completion

January 2004

Keywords

Biology, Cell|Health Sciences, Oncology

Degree

Ph.D.

Abstract

It is generally accepted that cyclooxygenase (COX)-2 is involved in tumorigenesis. However, the molecular mechanisms by which COX-2 regulates tumorigenesis have not been clearly understood. Here we show that COX-2 signaling pathway regulates angiogenesis in the mammary gland and that is critical for mammary cancer progression. In COX-2 overexpressed mammary gland, microvessel density increased prior to visible tumor growth and exponentially increased during tumor progression. In addition, PGE2, a major product of COX-2, stimulates expression of angiogenic regulatory genes in mammary tumor cells. These data suggest that PGE2 is a potent angiogenic inducer in mammary tumor-angiogenesis. PGE2 receptors (EP1,2,3, and 4), are differently expressed in the mammary gland. Expression of EP2 and 4 was upregulated in COX-2 induced mammary tumor and suppressed by inhibition of COX activity, suggesting the potential importance of EP2 and 4 in COX-2 induced mammary tumor-angiogenesis. To further investigate the roles of EP receptors in tumor-angiogenesis, we analyzed angiogenic response in three tumor cell lines isolated from COX-2 induced mammary tumors. EP2 null cell line showed very little induction of VEGF whereas EP2 expressing cell lines had strong induction of VEGF in response with PGE2. Interestingly, exogenous expression of EP2 in EP2 null cells recovered the ability of strong induction of VEGF expression by PGE2, suggesting that EP2 is required for PGE2 mediated VEGF induction. The treatment of H-89, PKA inhibitor in EP2 overexpressed cells abolished PGE2 mediated VEGF induction, suggesting that PKA is in downstream of PGE 2/EP2 mediated VEGF induction. Taken together, Our results indicate that PGE2, a major product released from mammary epithelial cells expressing COX-2 stimulates angiogenesis via EP2 signaling and thus, in part, contributes to mammary tumor progression. ^