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 dominantnegative (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.

BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

“…Consistent with reports of the involvement of BMP signaling in tumor growth and metastasis (12,15,19,(22)(23)(24)(25), we observed reduced levels of BMP4 in higher grade human breast cancers and noted that lower BMP4 mRNA expression in human breast tumors correlated with poor disease-free survival in patients (Supplementary Fig. S2A and S2B).…”

“…However, different results are seen when BMP signaling is examined in vivo. Disruption of BMPR2, the receptor for BMP2, 4, and 7, leads to epithelial hyperplasia and formation of polyps in the colon (22) and to enhanced metastasis in mice transgenic for MMTV-PyMT (23). Consistent with this, expression of constitutively active BMPR1B in mammary tumor cells suppresses metastasis to lung (24).…”

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

“…Although controversial, use of the high dose recombinant BMP2 in patients has been linked with increased cancer rates (31)(32)(33). In contrast, loss of BMP signaling via BMP receptor mutations/deletion is associated with increased tumorigenesis and metastasis (34,35). The contradictory roles of excess BMP exposure versus receptor loss demonstrate the complexity of the pathway.…”

Effects of recombinant human bone morphogenetic protein 7 (rhBMP-7) on the behaviour of oral squamous cell carcinoma: a preliminary in vitro study

“…Expression of BMPR2 was inversely correlated with the presence of metastases in bone, 11 and impaired BMPR2 function and extensive lung metastases have also been shown in a mouse model of breast cancer. 13 Further research is required to elucidate the interaction between rhBMP-7 and BMPR, and downstream signalling, or to show whether a BMPR blockade would abolish this inhibitory effect. In Smad4 knockout mice, a lack of BMP receptor signalling pathways resulted in increased proliferation of mammary duct 14 and cutaneous carcinomas.…”