title: Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators.
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.
authors.affiliation: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Owens
authors.forename: Michael W
authors.initials: MW
authors.lastname: Pickup
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Novitskiy
authors.forename: Anna
authors.initials: A
authors.lastname: Chytil
authors.forename: Agnieszka E
authors.initials: AE
authors.lastname: Gorska
authors.forename: Mary E
authors.initials: ME
authors.lastname: Aakre
authors.forename: James
authors.initials: J
authors.lastname: West
authors.forename: Harold L
authors.initials: HL
authors.lastname: Moses
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D000952:Antigens, Polyomavirus Transforming; D018925:Chemokines; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II