Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Tarragona, Maria; Pavlović, Milica; Arnal-Estapé, Anna; Urosevic, Jelena; Morales, M.L González; Guiu, Marc; Planet, Evarist; González‐Suárez, Eva; Gomis, Roger R.

doi:10.1074/jbc.m112.355834

Cited by 62 publications

(58 citation statements)

References 43 publications

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“…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).…”

Section: Bmp4 Suppresses Leukocytosis and Splenomegaly Induced By Metsupporting

confidence: 91%

“…Consistent with this, expression of constitutively active BMPR1B in mammary tumor cells suppresses metastasis to lung (24). Furthermore, BMP inhibitors Coco and Noggin, respectively, promote the colonization of mammary tumor cells in the lung (24), and metastasis to bone (25). Thus, while BMPs may act on tumor cells in culture with a diversity of outcomes, paracrine signaling to the tumor environment is lacking in tissue culture and impact on metastasis can be shown only using in vivo models.…”

Section: Introductionmentioning

confidence: 69%

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

et al. 2014

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The TGFb growth factor family member BMP4 is a potent suppressor of breast cancer metastasis. In the mouse, the development of highly metastatic mammary tumors is associated with an accumulation of myeloid-derived suppressor cells (MDSC), the numbers of which are reduced by exogenous BMP4 expression. MDSCs are undetectable in na€ ve mice but can be induced by treatment with granulocyte colony-stimulating factor (G-CSF/Csf3) or by secretion of G-CSF from the tumor. Both tumor-induced and G-CSF-induced MDSCs effectively suppress T-cell activation and proliferation, leading to metastatic enhancement. BMP4 reduces the expression and secretion of G-CSF by inhibiting NF-kB (Nfkb1) activity in human and mouse tumor lines. Because MDSCs correlate with poor prognosis in patients with breast cancer, therapies based on activation of BMP4 signaling may offer a novel treatment strategy for breast cancer. Cancer Res; 74(18); 5091-102. Ó2014 AACR.

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Section: Bmp4 Suppresses Leukocytosis and Splenomegaly Induced By Metsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 69%

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

et al. 2014

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“…Our clinical cohort demonstrated a significantly lower expression of FST in primary tumours that metastasised to bone. Overexpression of another BMP antagonist Noggin in breast cancer cells, is associated with the potential to develop osteolytic lesions in bone (32). And when looking at serum markers in breast cancer patients (33), activin levels were reported to be significantly increased in breast cancer compared with age-matched control donors, those with bone metastases having significantly higher levels than patients without.…”

Section: Cancer Genomics and Proteomicsmentioning

confidence: 99%

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Zabkiewicz

Resaul

Hargest

et al. 2017

CGP

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Abstract. Background Follistatin (FST) is a secreted extracellular regulatory protein that binds activin and, with less affinity, related TGFβ superfamily members such as bone morphogenetic proteins (BMPs), preventing access to their receptors (1, 2). Originally thought to act on the pituitary to regulate FSH release, FST has subsequently been noted in many other tissues, in particular co-localising with activin resulting in autocrine and paracrine cellular regulation (1, 3). As an antagonist of activin, FST has diverse regulatory roles in embryogenesis, tissue differentiation and repair, gonadal function and inflammatory and immune processes (3, 4).Three major FST isoforms can be produced, namely FST288 (from splice variant mRNA precursor FST317), FST315 (from splice variant mRNA precursor FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus (5). These three main FST isoforms can also be glycosylated to yield six further FST isoforms (6). FST288 and FST315 are differentially expressed in human tissues, but FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (6, 7) .The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8-11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin. Thus, the overall result of activin/FST action in cancer may be both context and cell type specific (3, 6).In the breast, FST is expressed in the normal mammary gland and in different breast proliferative diseases, with additional experimental evidence suggesting that FST can modulate the breast cancer cell cycle (3,(12)(13)(14). However, its role in breast cancer growth and metastasis is far from clear. In this study we demonstrated a clinical correlation between FST expression and survival in breast cancer, and that overexpression of FST in vitro reduces invasion of breast cancer cells. Patients and MethodsCell lines and patient tissue samples. Human breast cell lines MCF-7,MDA MB 231, ZR-751, BT 549 and BT-20 were obtained from and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum and antibiotics (PAA Laboratories Ltd., Somerset, UK). Cells were incubated at 37˚C in 5% CO 2 at 95% humidity.Breast cancer tissue and normal breast tissue samples were collected during surgery at the University Hospital of Wales. In total, 93 tumour samples and 30 normal breast tissue samples were obtained from patients who were enrolled in the study. The tissues obtained during surgery were snap-frozen in liquid nitrogen and stored at −80˚C.

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“…For example, the BMP ligand antagonist Coco enhances the self-renewal capability of metastasis-initiating breast cancer cells within the lung, and knockdown of Coco in MDA-MB-231 cells was sufficient to block lung metastasis (57). Overexpression of another BMP inhibitor, Noggin, can enhance the ability of breast cancer cells to form bone metastases (58). In addition, BMP4 has recently been attributed tumor-suppressive functions via its ability to block the activity of infiltrating myeloid-derived suppressor cells (MDSCs) (59).…”

Section: Discussionmentioning

confidence: 99%

Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

Cyr-Depauw

Northey

Tabariès

et al. 2016

Molecular and Cellular Biology

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ShcA is an important mediator of ErbB2-and transforming growth factor ␤ (TGF-␤)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-␤ stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling. Breast cancer is a heterogeneous disease that can be subdivided into distinct molecular subtypes through the integration of gene expression and genomics data (1, 2). While ErbB2 ϩ breast cancers are considered a poor-prognosis subtype (3), other signaling pathways can further modulate their malignant phenotypes. The transforming growth factor ␤ (TGF-␤) family is a prominent example that has been shown to enhance the migratory, invasive, and metastatic abilities of ErbB2 ϩ breast cancer cells (4-7). We have previously demonstrated that the ShcA adaptor protein plays an important role, downstream of TGF-␤ and ErbB2 signaling pathways, in mediating these cellular responses (8, 9). Loss of ShcA expression in ErbB2-expressing cells significantly reduced tumor growth, which was the result of reduced proliferation, diminished endothelial cell recruitment, and elevated apoptosis (9). In the present study, through the use of microarray based transcriptional profiling, we identified elevated levels of chordin-like 1 (Chrdl1) in ErbB2 ϩ breast cancer cells following TGF-␤ stimulation; however, this upregulation of Chrdl1 occurs only in the context of diminished ShcA levels.Bone morphogenetic proteins (BMPs) are secreted cytokines that belong to the TGF-␤ family of proteins, and their aberrant expression is observed in numerous cancers, including breast cancer (10). However, much like the TGF-␤ isoforms, there are conflicting reports on whether BMPs exert pro-or antitumorigenic effects on cancer cells (11,12). In breast cancer, BMP4 has been shown to promote cancer cell migration and invasion (13-16). Similarly, BMP7 induces breast cancer cell proliferation, migration/invasion, and metastasis (17, 18). Interestingly, BMP4 an...

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Identification of NOG as a Specific Breast Cancer Bone Metastasis-supporting Gene

Cited by 62 publications

References 43 publications

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

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

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

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