Bone morphogenetic protein 7 is widely overexpressed in primary breast cancer

Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Finland.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 04/2006; 45(4):411-9. DOI: 10.1002/gcc.20307
Source: PubMed


Bone morphogenetic proteins (BMP) make up a family of extracellular signaling molecules that play a critical role in vertebrate development and both inhibit and stimulate growth in cancer cells. BMP7 was recently identified in our genomewide copy number and expression survey as being activated through amplification in breast cancer cell lines. In the present study, we further explored BMP7 gene copy number and expression changes in 22 breast cancer cell lines and 146 primary breast tumors. FISH analysis revealed that BMP7 copy number varied greatly from one cell line to another, with three cell lines showing extremely high-level amplification. Among primary tumors, BMP7 copy number was increased in 16% of the cases. BMP7 mRNA expression was determined in the cell lines and in a subset of 44 tumor samples by RT-PCR or quantitative real-time RT-PCR, respectively. Despite elevated mRNA levels in cancer cells, there was no significant association between copy number increase and mRNA expression, even though the highest expression was seen in cell lines and tumors with increased BMP7 copy number. Most interestingly, immunohistochemical analysis revealed BMP7 protein staining in all 11 breast cancer cell lines examined and strongly elevated BMP7 protein expression in 71.4% of the tumor samples as compared to normal mammary epithelium. Our results illustrate the frequent involvement of BMP7 alterations in breast cancer and especially highlight overexpression of the BMP7 protein in a very large fraction of primary breast tumors, thus suggesting a possible functional role for BMP7 in breast cancer development.

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    • "These two BMPs were selected based on their essential role in breast cancer, which we and others have demonstrated in recent years [9-11]. Both ligands are highly expressed in primary breast carcinomas as well as in breast cancer cell lines [12-14,16,17]. BMP7 expression was also shown to be associated with early bone metastasis [15]. "
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    ABSTRACT: Bone 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. Both 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. All 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.
    BMC Medical Genomics 11/2011; 4(1):80. DOI:10.1186/1755-8794-4-80 · 2.87 Impact Factor
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    • "BMP7 is present in cancers, including breast, prostate, and colon cancers, in which it is implicated in regulating cancer cell proliferation.7–9 Overexpression of BMP7 mRNA in colorectal cancer patients was significantly associated with poor prognosis and low overall survival.10 "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) are secreted signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily of growth factors. Recent studies have shown that the influence of the expression of BMP7 was altered in several tumors. The purpose of the current study was to examine the expression of BMP7 in esophageal squamous cell carcinoma and to clarify the clinical impact of BMP7 expression in esophageal squamous cell carcinoma (ESCC). A total of 180 patients with ESCC who underwent surgical resection from 1991 to 2004 were eligible for this study. The expression of BMP7 in esophageal tumor tissues was examined immunohistochemically. BMP7 expression was found in the cytoplasm of cancer cells. BMP7 positivity was observed in 61.7% of tumors. The BMP7-positive group had deeper progression, more advanced stages, and greater venous invasion than those without BMP7 expression (p < 0.001, p < 0.005, and p < 0.0005, respectively). In addition, expression of BMP7 correlated with poorer prognosis (p < 0.0005). Multivariate analysis showed that BMP7 expression status was an independent prognostic factor (p < 0.05). Patients with expression of BMP7 in ESCC had high malignant potential. BMP7 could be a useful prognostic marker for patients with ESCC.
    Annals of Surgical Oncology 09/2011; 19(6):2066-71. DOI:10.1245/s10434-011-2024-5 · 3.93 Impact Factor
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    • "Moreover, in kidney, it is related to MET and reverses chronic renal injury (Zeisberg et al, 2003). On the other hand, BMP-7 expression has been identified and clinical features of BMP-7 expression in several human cancers such as osteosarcoma, malignant melanoma, breast cancer, prostate cancer, colorectal cancer and renal cell cancer have been discussed (Sulzbacher et al, 2002; Masuda et al, 2004; Alarmo et al, 2006; Kwak et al, 2007; "
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    ABSTRACT: Bone morphogenetic protein-7 (BMP-7) is a signalling molecule belonging to the transforming growth factor--superfamily. Recent studies have demonstrated the clinical impact of BMP-7 expression in various human cancers. However, there have been few reports detailing this in gastric cancer. We immunohistochemically investigated the expression of BMP-7 in 233 gastric cancer patients to disclose the clinicopathological features of BMP-7-positive gastric cancer. Immunohistochemically, in human gastric cancer, BMP-7 expression was identified in cellular membranes but also in the cytoplasm of cancer cells. Bone morphogenetic protein-7-positive expression was found in 129 of 233 patients (55%). Bone morphogenetic protein-7 expression was correlated with tumour size, nodal involvement, lymphatic invasion, venous invasion and histology (P<0.05). Bone morphogenetic protein-7 expression was significantly correlated with patient postoperative outcome, especially in the undifferentiated group. Multivariate analysis revealed BMP-7 expression as one of the independent prognostic factors next to the depth of invasion and nodal involvement (P<0.01). From the data collected, it would be appropriate to conclude on the possible regulation of gastric cancer progression by autocrine or paracrine BMP-7 loops. We can use BMP-7 expression as one of the strong predictors of risk of tumour recurrence in gastric cancer.
    British Journal of Cancer 02/2011; 104(4):714-8. DOI:10.1038/sj.bjc.6606075 · 4.84 Impact Factor
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