Abstract 3445: Targeting Thromboxane A2 receptor (TP) to block breast cancer metastasis

Abstract

Abstract The thromboxane A2 (TXA2) receptor, TP, is a G-protein coupled receptor. Previous studies in our lab have shown that the TP pathway regulates tumor cell cytoskeleton and TP activation induces rapid tumor cell contractions through small GTPase RhoA activation. Conversely, TP depletion reduces the metastatic dissemination of breast cancer cells in vivo by blocking the extravasation of tumor cells. Humans express two TP isoforms, TPγ and TPα. We report here that elevated TPγ expression is associated with metastasis in patients with breast cancer. While TPγ is expressed in all breast cancer cell lines that we examined, TPγ is only expressed in malignant cell lines, indicates that TPγ plays a role in breast cancer progression. Treatment with a selective TPγ inhibitor (CAY10535) blocks TP agonist (U46619) induced cell body contraction and RhoA activation. Additionally, TPγ inhibitor reduces migratory capacity and invasiveness in human breast cancer cell lines. Our previous work has shown that active TP is required for efficient extravasation of tumor cells in vivo; in this study, we further demonstrate that mice treated with SQ29548 (a high affinity TP antagonist) prior to tumor cell injection developed fewer metastatic lesions than the mice treated with SQ29548 after tumor cell injection. In all, our study indicated that TPγ can be targeted to reduce the risk of breast cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3445. doi:1538-7445.AM2012-3445