Changes in the expression of plasma proteins associated with thrombosis in BRCA1 mutation carriers

Custodio, Ana; López‐Farré, Antonio; Zamorano-León, José J.; Mateos-Cáceres, Petra J.; Macaya, Carlos; Caldés, Trinidad; Hoya, Miguel de la; Olivera, E.; Puente, Javier; Dı́az-Rubio, Eduardo; Pérez‐Segura, Pedro

doi:10.1007/s00432-012-1161-y

Cited by 18 publications

(15 citation statements)

References 53 publications

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“…Proteins such as VDBP and A1BG were differentially altered in a manner consistent with chemoprevention (13)(14)(15)(16). VDBP was found to be upregulated, whereas A1BG was downregulated in response to increasing levels of n-3 fatty acids.…”

Section: Resultsmentioning

confidence: 81%

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

Skibinski

Thompson

Das

et al. 2013

Cancer Prevention Research

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We used a proteomic approach to gain insights into the mechanisms of protection at the protein level by a high n-3:n-6 ratio in the absence and presence of Tamoxifen. Four groups were treated with 1-methyl-1-nitrosourea (MNU) and fed the following diets with varied n-3:n-6 ratios; group 1 ¼ 1:1; groups 2 and 3 ¼ 10:1 and 25:1, respectively; group 4: (25:1) plus Tamoxifen (1 mg/kg diet). The plasma from six rats/group was pooled and analyzed with the isobaric tags for relative and absolute quantitation method; 148 proteins were identified with 95% confidence by ProteinPilot 4.0. In plasma of rats fed 10:1, 25:1 n-3:n-6, and 25:1 plus Tamoxifen, the number of proteins that met our criteria (P 0.05, error factor 2) were 10, 14, and 19 proteins, respectively. Selected proteins were further validated by Western blotting. Compared to 1:1, both 10:1 and 25:1 diets upregulated vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein, which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1, the 25:1 plus Tamoxifen diet downregulated apolipoprotein E, haptoglobin, and inter-a-inhibitor H4 heavy chain. Ingenuity pathway analysis determined that the trends of specific proteins were related to lipid metabolism in the 25:1 n-3:n-6 group, whereas the 25:1 n-3:n-6 plus Tamoxifen group included proteins involved in cancer and inflammation. Our results show that several proteins were altered in a manner consistent with chemoprevention. Such proteins may serve as biomarkers to monitor efficacy of n-3 and Tamoxifen in future clinical chemoprevention trials. Cancer Prev Res; 6(9); 979-88. Ó2013 AACR.

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Section: Resultsmentioning

confidence: 81%

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

Skibinski

Thompson

Das

et al. 2013

Cancer Prevention Research

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“…Red bars indicate greater abundance in tissue from patients with high MD: apolipoprotein D (APOD), a breast cyst fluid component and potentially a progesterone transporter [ 65 ], which is expressed in ductal carcinoma [ 66 ]; prolactin-inducible protein (PIP), a fibronectin-degrading aspartyl proteinase [ 67 ], which is frequently expressed in androgen receptor-positive breast tumours [ 68 ]; polymeric immunoglobulin receptor (PIGR), an epithelial cell-surface-located [ 69 ] biomarker of metastatic breast cancer [ 70 ]; zinc-alpha-2-glycoprotein (AZGP1), which stimulates lipolysis in adipocytes and is expressed in up 50 % of human breast cancers [ 71 ]; collagen XVI alpha 1 chain and periostin (COL16A1 and PSTN), extracellular matrix (ECM)-regulating proteins, which control collagen fibril interactions [ 50 – 52 ]; and two further proteins: immunoglobulin J (IGJ) and ACTN4, which have no known links to cancer or ECM remodelling [ 72 , 73 ]. Proteins with a greater abundance in low MD tissue include: myeloperoxidase (MPO), serum markers of breast cancer including the neutrophil activity marker myeloperoxidase [ 74 ]; S100A8 and S100A9 (proinflammatory regulators [ 75 , 76 ]), which play an as-yet poorly defined role in metastasis [ 77 , 78 ]; C5 (a proteolytic degradation product of complement C5 [ 79 ], S100A11), which facilitates keratinocyte differentiation; apolipoprotein C-I (APOC1), an inhibitor of lipoprotein/LDL receptor binding [ 80 ], which may promote chronic low-grade inflammation and breast cancer [ 81 ]; inter-alpha-trypsin inhibitor heavy chain H1 (H1ITIH1), a hyaluronan binding protein [ 82 ], which is implicated in inflammation and downregulated in breast cancer [ 83 ]; HRG, histidine-rich glycoprotein, which inhibits tumour vascularisation [ 84 , 85 ]; apolipoprotein A-I (APOA1), which is reported to be protective against breast cancer [ 86 ]; SERPINB6, an ECM protease inhibitor [ 54 ]; coagulation factor XIII A chain (F13A1), which inhibits degradation of collagen precursors [ 53 ]; glucose-6-phosphate isomerase (GPI), which modulates cancer cell phenotype [ 87 ]; apolipoprotein A-IV (APOA4) - blood plasma levels are significantly reduced in BRCA1 mutation carriers modulate [ 88 ]; laminin subunit beta-2 (LAMB2), a component of basement membranes, which is implicated in tumour angiogenesis [ 89 ]. Both serum paraoxonase/arylesterase 1 (PON1) and mitochondrial 60 kDa h...…”

Section: Resultsmentioning

confidence: 99%

Increased peri-ductal collagen micro-organization may contribute to raised mammographic density

et al. 2016

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BackgroundHigh mammographic density is a therapeutically modifiable risk factor for breast cancer. Although mammographic density is correlated with the relative abundance of collagen-rich fibroglandular tissue, the causative mechanisms, associated structural remodelling and mechanical consequences remain poorly defined. In this study we have developed a new collaborative bedside-to-bench workflow to determine the relationship between mammographic density, collagen abundance and alignment, tissue stiffness and the expression of extracellular matrix organising proteins.MethodsMammographic density was assessed in 22 post-menopausal women (aged 54–66 y). A radiologist and a pathologist identified and excised regions of elevated non-cancerous X-ray density prior to laboratory characterization. Collagen abundance was determined by both Masson’s trichrome and Picrosirius red staining (which enhances collagen birefringence when viewed under polarised light). The structural specificity of these collagen visualisation methods was determined by comparing the relative birefringence and ultrastructure (visualised by atomic force microscopy) of unaligned collagen I fibrils in reconstituted gels with the highly aligned collagen fibrils in rat tail tendon. Localised collagen fibril organisation and stiffness was also evaluated in tissue sections by atomic force microscopy/spectroscopy and the abundance of key extracellular proteins was assessed using mass spectrometry.ResultsMammographic density was positively correlated with the abundance of aligned periductal fibrils rather than with the abundance of amorphous collagen. Compared with matched tissue resected from the breasts of low mammographic density patients, the highly birefringent tissue in mammographically dense breasts was both significantly stiffer and characterised by large (>80 μm long) fibrillar collagen bundles. Subsequent proteomic analyses not only confirmed the absence of collagen fibrosis in high mammographic density tissue, but additionally identified the up-regulation of periostin and collagen XVI (regulators of collagen fibril structure and architecture) as potential mediators of localised mechanical stiffness.ConclusionsThese preliminary data suggest that remodelling, and hence stiffening, of the existing stromal collagen microarchitecture promotes high mammographic density within the breast. In turn, this aberrant mechanical environment may trigger neoplasia-associated mechanotransduction pathways within the epithelial cell population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0664-2) contains supplementary material, which is available to authorized users.

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“…A few of these were enriched in canonical cancer functions like signal transduction, cell proliferation and DNA metabolism, but also in coagulation and RNA processing. Blood coagulation was recently found to have important contributions to cancer pathogenesis [57], [58]. Similarly, RNA processing also has been recently shown to be involved in cancer pathogenesis [59], [60].…”

Section: Resultsmentioning

confidence: 99%

Deriving a Mutation Index of Carcinogenicity Using Protein Structure and Protein Interfaces

et al. 2014

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With the advent of Next Generation Sequencing the identification of mutations in the genomes of healthy and diseased tissues has become commonplace. While much progress has been made to elucidate the aetiology of disease processes in cancer, the contributions to disease that many individual mutations make remain to be characterised and their downstream consequences on cancer phenotypes remain to be understood. Missense mutations commonly occur in cancers and their consequences remain challenging to predict. However, this knowledge is becoming more vital, for both assessing disease progression and for stratifying drug treatment regimes. Coupled with structural data, comprehensive genomic databases of mutations such as the 1000 Genomes project and COSMIC give an opportunity to investigate general principles of how cancer mutations disrupt proteins and their interactions at the molecular and network level. We describe a comprehensive comparison of cancer and neutral missense mutations; by combining features derived from structural and interface properties we have developed a carcinogenicity predictor, InCa (Index of Carcinogenicity). Upon comparison with other methods, we observe that InCa can predict mutations that might not be detected by other methods. We also discuss general limitations shared by all predictors that attempt to predict driver mutations and discuss how this could impact high-throughput predictions. A web interface to a server implementation is publicly available at http://inca.icr.ac.uk/.

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Changes in the expression of plasma proteins associated with thrombosis in BRCA1 mutation carriers

Abstract: It is suggested that independently of breast cancer generation, BRCA1-encoded gene alterations are associated with changes in the expression of circulating proteins associated with thrombosis and coagulation.

Cited by 18 publications

References 53 publications

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

Increased peri-ductal collagen micro-organization may contribute to raised mammographic density

Deriving a Mutation Index of Carcinogenicity Using Protein Structure and Protein Interfaces

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