Towards discovery‐driven translational research in breast cancer

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It has become clear that growth and progression of breast tumor cells not only depend on their malignant potential but also on factors present in the tumor microenvironment. Of the cell types that constitute the mammary stroma, the adipocytes are perhaps the least well studied despite the fact that they represent one of the most prominent cell types surrounding the breast tumor cells. There is compelling evidence demonstrating a role for the mammary fat pad in mammary gland development, and some studies have revealed the ability of fat tissue to augment the growth and ability to metastasize of mammary carcinoma cells. Very little is known, however, about which factors adipocytes produce that may orchestrate these actions and how this may come about. In an effort to shed some light on these questions, we present here a detailed proteomic analysis, using two-dimensional gel-based technology, mass spectrometry, immunoblotting, and antibody arrays, of adipose cells and interstitial fluid of fresh fat tissue samples collected from sites topologically distant from the tumors of high risk breast cancer patients that underwent mastectomy and that were not treated prior to surgery. A total of 359 unique proteins were identified, including numerous signaling molecules, hormones, cytokines, and growth factors, involved in a variety of biological processes such as signal transduction and cell communication; energy metabolism; protein metabolism; cell growth and/or maintenance; immune response; transport; regulation of nucleobase, nucleoside, and nucleic acid metabolism; and apoptosis. Apart from providing a comprehensive overview of the mammary fat proteome and its interstitial fluid, the results offer some insight as to the role of adipocytes in the breast tumor microenvironment and provide a first glance of their molecular cellular circuitry. In addition, the results open new possibilities to the study of obesity, which has a strong association with type 2 diabetes, hypertension, and coronary heart disease. Molecular & Cellular Proteomics 4: 492-522, 2005.During the last years there have been numerous reports indicating that growth and progression of breast as well as other tumor cells depend not only on their malignant potential but also on stromal factors present in the tumor microenvironment, the insoluble extracellular matrix as well as cell-cell interactions (Refs.

Section: Protein Profiling Of Whole Fat Tissuementioning

confidence: 99%

Section: Cytokines and Growth Factors Secreted By Adipocytesmentioning

confidence: 99%

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Identification of Extracellular and Intracellular Signaling Components of the Mammary Adipose Tissue and Its Interstitial Fluid in High Risk Breast Cancer Patients

Celis

Moreira

Cabezón

et al. 2005

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208

164

“…It is also possible to generate data on many different individual patients to evaluate heterogeneity of tissue profiles. The correlation between genotype and phenotype is still poorly understood and presents a critical challenge to functionally explore mechanisms underlying normal development and disease (46). The phenotypical appearance as seen in a tissue section is evidently based on pattern of expressed proteins within a cell as well as composition of the surrounding micro-environment.…”

Section: Relevance For Clinical Proteomicsmentioning

confidence: 99%

Antibody-based Proteomics for Human Tissue Profiling

Uhlén

Pontén

2005

263

161

Here, we describe the use of antibody-based proteomics involving the generation of protein-specific antibodies to functionally explore the human proteome. The antibodies can be used for analysis of corresponding proteins in a wide range of assay platforms, including i) immunohistochemistry for detailed tissue profiling, ii) specific affinity reagents for various functional protein assays, and iii) capture ("pull-down") reagents for purification of specific proteins and their associated complexes for structural and biochemical analyses. In this review, the use of antibodies for such analysis will be discussed with focus on the possibility to create a descriptive and comprehensive protein atlas for tissue distribution and subcellular localization of human proteins in both normal and disease tissues.

“…The challenge for antibody-based proteomics is to move from a conventional protein-by-protein approach into a high throughput mode to allow chromosome wide analysis (6,7). Technical challenges involve both the antigen production and the subsequent generation and characterization of the antibodies.…”

mentioning

confidence: 99%

A Human Protein Atlas for Normal and Cancer Tissues Based on Antibody Proteomics

Uhlén

Björling²,

Agaton³

et al. 2005

1,276

1,021

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, ϳ400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.