Abstract 922: Disruption of bone morphogenetic protein receptor 2 accelerates mammary carcinoma metastasis to the lung

Abstract

Abstract Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth inhibition in cancers as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have both tumor suppressive and promoting effects. We sought to determine whether disruption of the Bone Morphogenetic Protein Receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen (PyVmT). Mice expressing PyVmT under the mammary specific MMTV promoter were combined with mice that have Doxycycline inducible expression of a dominant negative (DN) BMPR2. We did not observe any differences in tumor latency. However, when we measured pulmonary metastases, we found that mice expressing the BMPR2-DN had a five fold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN expressing tumor cells had higher rates of proliferation and epithelial to mesenchymal transition (EMT). We also identified unique changes in the tumor microenvironment, which included inflammatory cells and secreted chemokines/ cytokines that accompanied BMPR2-DN expressing tumors. We identified several molecules including ccl-9 (MIP1γ), which was elevated in BMPR2-DN expressing tumors. Ccl-9 has recently been shown to be an important chemokine in the recruitment of myeloid cells that promote metastatic progression. We discovered that tumor cells treated exogenously with BMP4 ligand repressed ccl-9 mRNA and that this repression was limited in cells expressing BMPR2-DN. We conclude that BMPR2 has tumor suppressive function in mammary epithelia and that disruption can accelerate mammary carcinoma metastases via paracrine stimulation of myeloid cells in the tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 922. doi:10.1158/1538-7445.AM2011-922