Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators
Open Access
- 16 May 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (8), 2814-2819
- https://doi.org/10.1073/pnas.1101139108
Abstract
Bone morphogenetic proteins (BMPs) are members of the TGF-β 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 carcinoma cells as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers and may have tumor suppressive and promoting effects. We sought to determine whether disruption of the BMP receptor 2 (BMPR2) would alter mammary tumor progression in mice that express the Polyoma middle T antigen. Mice expressing Polyoma middle T antigen under the mouse mammary tumor virus 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, mice expressing the BMPR2-DN had a fivefold increase in lung metastases. We characterized several cell autonomous changes and found that BMPR2-DN–expressing tumor cells had higher rates of proliferation. We also identified unique changes in inflammatory cells and secreted chemokines/cytokines that accompanied BMPR2-DN–expressing tumors. By immunohistochemistry, it was found that BMPR2-DN primary tumors and metastases had an altered reactive stroma, indicating specific changes in the tumor microenvironment. Among the changes we discovered were increased myeloid derived suppressor cells and the chemokine CCL9. BMP was shown to directly regulate CCL9 expression. We conclude that BMPR2 has tumor-suppressive function in mammary epithelia and microenvironment and that disruption can accelerate mammary carcinoma metastases.Keywords
This publication has 35 references indexed in Scilit:
- Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse modelProceedings of the National Academy of Sciences of the United States of America, 2010
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- Learning therapeutic lessons from metastasis suppressor proteinsNature Reviews Cancer, 2009
- Conversion of the Nipple to Hair-Bearing Epithelia by Lowering Bone Morphogenetic Protein Pathway Activity at the Dermal-Epidermal InterfaceThe American Journal of Pathology, 2008
- Abrogation of TGFβ Signaling in Mammary Carcinomas Recruits Gr-1+CD11b+ Myeloid Cells that Promote MetastasisCancer Cell, 2008
- Cooperation of signalling pathways in embryonic mammary gland developmentNature Reviews Genetics, 2007
- Bone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growthBiochemical and Biophysical Research Communications, 2007
- A comprehensive expression survey of bone morphogenetic proteins in breast cancer highlights the importance of BMP4 and BMP7Breast Cancer Research and Treatment, 2006
- Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth MuscleCirculation Research, 2004
- Bone Morphogenetic Protein-2 Blocks MDA MB 231 Human Breast Cancer Cell Proliferation by Inhibiting Cyclin-Dependent Kinase-Mediated Retinoblastoma Protein PhosphorylationBiochemical and Biophysical Research Communications, 2000