Proteomic approaches to early detection of breast cancer
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KeywordsBreast Cancer Functional Genomic Cyst Fluid Membrane Blebbing Basic Discovery
The completion of the human genome as well as the explosion of novel technologies within genomics, proteomics and functional genomics promise to have a major impact on clinical practice, as these technologies are expected to accelerate the translation of basic discoveries to the clinical practice. In particular, proteomic technologies are expected to play a key role in the study and treatment of cancer as they provide invaluable resources to define and characterize regulatory and functional networks, to investigate the precise molecular defect in diseased tissues and biological fluids, and to develop specific reagents to precisely pinpoint a particular disease or stage of a disease. For drug discovery, proteomics assist with powerful tools for identifying new clinically relevant drug targets, and provide functional insight for drug development.
Today, the application of novel technologies from proteomics and functional genomics to the study of cancer is rapidly shifting to the analysis of clinically relevant samples such as fresh biopsy specimens and fluids, as their use will accelerate the translation of basic discoveries. Being a patient-oriented organisation, The Danish Cancer Society catalysed in 2002 the creation of a multidisciplinary research environment, the DCTB, to fight breast cancer. The DCTB hosts scientists working in various areas of preclinical cancer research (cell cycle control, invasion and microenvironmental alterations, apoptosis, cell signalling, and immunology) with clinicians (surgeons, oncologists) and pathologists in an integrated, mission-oriented, discovery-driven translational research environment. The unifying concept behind our experimental strategy is the use of multiple experimental paradigms for the prospective analysis of clinically relevant samples obtained from the same patient, along with the systematic integration of the biological and clinical data.
Here I will describe our efforts to apply proteomics approaches to search for markers for early detection of breast cancer using the newly characterized interstitial fluids recovered from fresh tissue biopsies of both normal (NIF) and tumour (TIF) origin. The protein composition of the fluids is strikingly different to that of serum and cyst fluids, although they share some of their major components. The TIF is highly enriched in proteins that are either secreted via the classic endoplasmic reticulum/Golgi pathway, shed by membrane vesicles (membrane blebbing), or externalized by plasma membrane transporter. Hundreds of primary translation products, as well as post-translational modifications, have so far been identified using a combination of procedures that include mass spectrometry, two-dimensional gel immunoblotting, and cytokine and signalling pathway-specific antibody arrays. The workflow to biomarker discovery as well as recent developments will be discussed.