Abstract 5622: Effect of novel RhoC inhibitor on breast cancer progression and metastasis in vivo

Abstract

Abstract Introduction: The oncogene RhoC GTPase is overexpressed in highly aggressive inflammatory breast cancer (IBC) and increases cellular motility and invasiveness in mammary tissue by interacting with downstream effectors to reorganize cytoskeletal elements in the cell. A small molecule inhibitor of RhoC-effector interaction has been identified. This antagonist decreases proliferation and inhibits motility of IBC cells in vitro. Here we evaluate the in vivo effects of the novel RhoC antagonist in a transgenic mouse model of breast cancer. Methods: The PyMT-RhoC transgenic mouse model was used in this study. This double transgenic strain was created by crossing the polyoma middle T antigen (PyMT) breast cancer model to a RhoC-overexpressing strain driven by the mouse mammary tumor virus (MMTV) promoter. The RhoC inhibitor was administered by intraperitoneal injection beginning at 50 days of age. Tumor size was monitored throughout treatment. At the end of the treatment, mammary glands, tumors, and lungs were extracted, fixed, sectioned, and stained with H&E. Results: PyMT-RhoC mice treated with the RhoC inhibitor showed a statistically significant delay in time of onset of the primary tumor and exhibited slower growth of the primary tumor compared to the control group. Western blot showed decreased RhoC protein levels in the treated PyMT-RhoC group relative to control, suggesting that the drug's in vivo activity includes reducing RhoC protein expression. Finally, as determined through H&E staining of lung sections, tumor metastasis to the lungs was decreased in the treated group compared to age-matched controls. Conclusions: We conclude that this novel RhoC antagonist shows promise in vivo as an inhibitor of mammary tumor proliferation and metastasis, and has the potential to be a clinically relevant treatment for inflammatory breast cancer. 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 5622. doi:1538-7445.AM2012-5622