Abstract
Bone Morphogenetic Proteins (BMPs) are secreted cytokines that are part of the Transforming Growth Factor β (TGFβ) superfamily. BMPs have been shown to be highly expressed in human breast cancers, and loss of BMP signaling in mammary carcinomas has been shown to accelerate metastases. Interestingly, other work has indicated that stimulation of dermal fibroblasts with BMP can enhance secretion of pro-tumorigenic factors. Furthermore, treatment of carcinoma-associated fibroblasts (CAFs) derived from a mouse prostate carcinoma with BMP4 was shown to stimulate angiogenesis. We sought to determine the effect of BMP treatment on mammary fibroblasts. A large number of secreted pro-inflammatory cytokines and matrix-metallo proteases (MMPs) were found to be upregulated in response to BMP4 treatment. Fibroblasts that were stimulated with BMP4 were found to enhance mammary carcinoma cell invasion, and these effects were inhibited by a BMP receptor kinase antagonist. Treatment with BMP in turn elevated pro-tumorigenic secreted factors such as IL-6 and MMP-3. These experiments demonstrate that BMP may stimulate tumor progression within the tumor microenvironment.
Highlights
Within the family of Transforming Growth Factor b (TGFb) are Bone Morphogenetic Proteins (BMPs), which can induce differentiation, growth arrest, apoptosis and many other distinct responses [1,2]
We investigated the ability of recombinant BMP4 to induce growth arrest by titering increasing amounts of BMP4 up to 100 ng/ml and did not observe a reduction in proliferation as measure by uptake of H3-Thymidine (Fig. 1A)
To further validate that mouse mammary fibroblasts were responding to BMP4 stimulation, real time-PCR (RT-PCR) was performed to measure mRNA changes in response to 24 hours of 100 ng/ml BMP4 treatment
Summary
Within the family of Transforming Growth Factor b (TGFb) are Bone Morphogenetic Proteins (BMPs), which can induce differentiation, growth arrest, apoptosis and many other distinct responses [1,2]. When ligands bind to either type I or type II serine/threonine kinase receptors, they phosphorylate Smad, Smad and/or Smad8 [4,5]. These Smads translocate in combination with Smad to the nucleus and regulate transcription of key target genes. One key element to the signaling behavior of BMP and TGFb in general is the ability to induce negative feedback. While measurement of a BMP transcriptional response is measured by target genes (Id1, Smad and Smad7), inhibitory Smad proteins (Smad and Smad7) are some of the most prominent targets of active BMP signaling [2]
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