Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells

Clement, Joachim H.; Raida, Martin; Sänger, Jörg; Bicknell, Roy; Li, Jingwen; Naumann, Anke; Geyer, A; Waldau, Anja; Hortschansky, Peter; Schmidt, Andreas; Höffken, K.; Wölft, Stefan; Harris, Adrian L.

doi:10.3892/ijo.27.2.401

Cited by 73 publications

(75 citation statements)

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“…BMP treatment can enhance cell migration in vitro in transformed and nontransformed mammary epithelial cells (4,5,7,14). Our findings show that an attenuation of BMP signaling can enhance migration and invasion.…”

Section: Discussionmentioning

confidence: 70%

“…In human breast cancer, recent evidence has demonstrated that overexpression of BMPs (specifically BMP4 and BMP7) correlates with advanced disease (12,13). It has also been shown that, when breast cancer cell lines are treated with BMP4, they have enhanced migration and invasion (4,5,7,14). BMP2 has been shown to promote breast cancer microcalcification (15).…”

mentioning

confidence: 99%

“…Treatment with BMPs in vitro has mainly mirrored the effects of TGF-β by inducing growth arrest and an epithelial-to-mesenchymal transition (EMT) (4,5). BMP ligands are widely expressed in the developing mammary gland (6).…”

mentioning

confidence: 99%

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Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

Owens

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Novitskiy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 99%

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Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

Owens

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Novitskiy

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…13; see Supplementary Fig. S2), BMP2 may affect malignancy via enhancement of cell migration and invasion (22,36). Therefore, we functionally assessed whether these malignant properties were BMP2-regulated in MPNST cell lines.…”

Section: Blocking Bmp2 Signaling By Ldn-193189 and Shrna Knockdown Immentioning

confidence: 99%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616-27. Ó2013 AACR.

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“…Several cytokines have also been reported to inhibit myeloma cell growth in different culture conditions, including bone morphogenetic proteins (BMPs) [10,11]. Despite BMP proapoptotic action on several myeloma cell lines and primary myeloma cells in vitro [12][13][14], other studies on different types of malignancies showed their tumor-promoting effects in vitro and in vivo [15][16][17][18][19][20]. Importantly, in vitro effects of BMPs need to be further investigated on human MM samples because primary myeloma cells in culture conditions are removed from the interactions with other cells within BM microenvironment which may regulate their response [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic proteins and receptors are over-expressed in bone-marrow cells of multiple myeloma patients and support myeloma cells by inducing ID genes

et al. 2010

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Bone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cells

Cited by 73 publications

References 0 publications

Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

Disruption of bone morphogenetic protein receptor 2 (BMPR2) in mammary tumors promotes metastases through cell autonomous and paracrine mediators

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Bone morphogenetic proteins and receptors are over-expressed in bone-marrow cells of multiple myeloma patients and support myeloma cells by inducing ID genes

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