Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2

Steinert, Susanne; Kroll, Torsten; Taubert, Isabel; Pusch, Larissa; Hortschansky, Peter; Höffken, K.; Wölfl, Stefan; Clement, Joachim H.

doi:10.1007/s00432-008-0396-0

Cited by 18 publications

(13 citation statements)

References 35 publications

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“…Our results are consistent with a study showing significant differences in gene expression between single and continuous application of BMP-2 to MCF-7 cells in vitro [24]. Our results are also consistent with a recent study suggesting that an excess of BMP-2 relative to matrix Gla protein (MGP) results in trans-differentiation of smooth muscle cells to osteochondrogenic precursors, leading to vasculature calcification [25].…”

Section: Discussionsupporting

confidence: 93%

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification

Liu

Misra

Lunsford

et al. 2009

Breast Cancer Res Treat

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Introduction The development of novel diagnostic agents for the detection of breast cancer microcalcifications requires a reliable animal model. Based on previous work from our group, we hypothesized that a single systemic injection of recombinant bone morphogenetic protein-2 (rBMP-2) could be used to create such a model. Methods The cDNA encoding mature human BMP-2 was expressed in BL21(DE3) bacteria, purified to homogeneity, and re-folded as a dimer. Bioactivity was confirmed using a C2C12 alkaline phosphatase assay. rBMP-2 was radiolabeled with 99mTc and its biodistribution and clearance were quantified after both intravenous (IV) and intraperitoneal (IP) injection. Fischer 344 rats bearing syngeneic R3230 breast tumors received a single intraperitoneal injection of rBMP-2 at a specified dose. Tumor microcalcification was quantified over time using micro single-photon emission computed tomography (SPECT) and micro computed tomography (CT). Results rBMP-2 could be expressed in E. coli at high levels, isolated at >95% purity, and refolded to a bioactive dimer. Beta-phase half-life was 30.5 min after IV administration and 47.6 min after IP administration. Renal excretion was the primary mode of clearance. A single IP injection of ≥ 50 μg rBMP-2 when tumors were not yet palpable resulted in dose-dependent microcalcification in 8 of 8 R3230 tumors. No calcification was found in control tumors, or in normal tissues and organs of animals injected with rBMP-2. Tumor calcification increased progressively between weeks 2 to 4 post-rBMP-2 injection. Conclusions A single IP injection of rBMP-2 in rats bearing a syngeneic breast cancer will produce dose-dependent and time-dependent microcalcifications. This animal model lays the foundation for the development of novel diagnostic radiotracers for breast cancer.

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Section: Discussionsupporting

confidence: 93%

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification

Liu

Misra

Lunsford

et al. 2009

Breast Cancer Res Treat

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“…The transcriptional responses of breast cancer cells to BMP signaling have been studied only minimally. More precisely, the effects of BMP2 and BMP7 treatments on transcription in MCF-7 and MDA-MB-468 breast cancer cell lines, respectively, have been analyzed using cDNA microarrays of limited content (from several hundreds to 14, 500 gene probes) [28-30]. In this study, we have therefore set up an experimental procedure to identify potential BMP target genes in breast cancer by studying the effects of two BMP ligands, BMP4 and BMP7, on genome-wide gene expression.…”

Section: Discussionmentioning

confidence: 99%

Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes

et al. 2011

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BackgroundBone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily of growth factors. They are known for their roles in regulation of osteogenesis and developmental processes and, in recent years, evidence has accumulated of their crucial functions in tumor biology. BMP4 and BMP7, in particular, have been implicated in breast cancer. However, little is known about BMP target genes in the context of tumor. We explored the effects of BMP4 and BMP7 treatment on global gene transcription in seven breast cancer cell lines during a 6-point time series, using a whole-genome oligo microarray. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data.ResultsBoth ligands had a strong effect on gene expression, although the response to BMP4 treatment was more pronounced. The cellular functions most strongly affected by BMP signaling were regulation of transcription and development. The observed transcriptional response, as well as its functional outcome, followed a temporal sequence, with regulation of gene expression and signal transduction leading to changes in metabolism and cell proliferation. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMPs, but also highlighted a synexpression group of genes for both ligands. Interestingly, the majority of the genes within these synexpression groups were shared by the two ligands, probably representing the core molecular responses common to BMP4 and BMP7 signaling pathways.ConclusionsAll in all, we show that BMP signaling has a remarkable effect on gene transcription in breast cancer cells and that the functions affected follow a logical temporal pattern. Our results also uncover components of the common cellular transcriptional response to BMP4 and BMP7. Most importantly, this study provides a list of potential novel BMP target genes relevant in breast cancer.

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“…Breast cancer cell resistance to apoptosis is increased by BMP2, and based on microarray studies, BMP2 influences apoptosis-related genes (Raida et al 2005a, Steinert et al 2008. Furthermore, migration and invasion of breast cancer cells are enhanced by BMP2 (Clement et al 2005).…”

Section: E-l Alarmo and A Kallioniemi: Bmps In Breast Cancermentioning

confidence: 99%

Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis?

Alarmo

Kallioniemi

2010

Endocrine-Related Cancer

102

100

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The human bone morphogenetic protein (BMP) family consists of over 20 growth factor proteins that are involved in bone formation and developmental processes. BMPs are extracellular signalling molecules that are able to regulate various cellular functions, proliferation, differentiation, apoptosis and migration. For the last 10 years, these powerful cytokines have increasingly been studied in several cancers, and aberrant expression patterns of BMPs have been reported. Functional studies have suggested that BMPs are involved in both cancer promotion and inhibition. The role these signalling molecules play in breast cancer is only starting to emerge: thus far, studies have been even contradictory. Different BMP ligands have been shown to decrease as well as increase cancer cell growth and migration. Furthermore, they are involved in bone metastases, which are a common feature in breast cancer. In this sense, BMPs resemble a closely related protein transforming growth factor b, which possesses a bidirectional role in cancer cell regulation. In this review, we focus on the current knowledge of BMP expression, functional roles and involvement in bone metastasis in breast cancer.

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Differential expression of cancer-related genes by single and permanent exposure to bone morphogenetic protein 2

Cited by 18 publications

References 35 publications

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification

A dose- and time-controllable syngeneic animal model of breast cancer microcalcification

Analysis of BMP4 and BMP7 signaling in breast cancer cells unveils time-dependent transcription patterns and highlights a common synexpression group of genes

Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis?

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