Abstract A56: Bone morphogenetic protein antagonist DMH1 inhibits metastasis in a mouse model of breast cancer

Abstract

Abstract Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) superfamily. BMPs have recently been shown to be overexpressed in human breast cancers; however, loss of BMP signaling in mammary carcinomas has also been shown to accelerate metastases. Human breast cancers display active BMP signaling by phosphorylated Smads 1, 5 and 8 in both the tumor and the stromal microenvironment. We hypothesized that inhibiting BMP signaling in both the tumor epithelium as well as the surrounding microenvironment would prevent tumor progression. To test this hypothesis we used DMH1, which is a selective and specific antagonist of the type I BMP receptor. Mice that express the MMTV.PyVmT oncogene were either treated with DMSO vehicle or DMH1 for six weeks following initial mammary tumor palpation. Following six weeks, animals were euthanatized and evaluated for lung metastases. Whole mount staining of lungs revealed a statically significant reduction in lung metastasis in DMH1 treated animals compared to vehicle treated (p-value = 0.03). Primary tumors demonstrated reduced proliferation (BrdU incorporation) and increased apoptosis (cleaved-caspase-3) when treated with DMH1. RNA isolated from peripheral blood at the time of sacrifice indicated decreased circulating tumor cells measured by real-time PCR. Overall, the BMP pathway represents an understudied pathway that may be suitable for targeted therapy in breast cancer. Citation Format: Philip Owens, Michael W. Pickup, Agnieszka E. Gorska, Sergey V. Novitskiy, Charles C. Hong, Harold L. Moses. Bone morphogenetic protein antagonist DMH1 inhibits metastasis in a mouse model of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A56.