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Analysis of Proteomic Patterns in Breast Cancer and Associated Tumor Stroma
Background: Mass spectrometry (MS) is a powerful tool for the rapid and precise identification of proteins in complex mixtures or in situ in tissues and cells. Direct analysis of the proteome by MS has the potential to address the global changes controling the heterogeneous biology of breast cancer (BC). Complex interactions among proteins in both tumor epithelium and its desmoplastic stroma are likely involved in promoting breast cancer development and progression. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) coupled with laser capture microdissection is an ideal approach to separately profiling the epithelial and stromal components of BC.
Hypothesis: Differentially expressed proteins among benign and malignant epithelium and stroma reflect the critical molecular alterations leading to breast cancer development and progression. Identification of these unique protein signatures and subsequent characterization their component proteins will identify novel tumor specific markers and potential drug targets.
Specific Aims: 1) To generate protein expression profiles of cancer and normal mammary epithelium and to use class prediction models to identify novel proteins with a pathogenic role in BC. 2) To determine the protein expression profiles of tumor and normal breast stromas using MALDI-TOF MS and to use class prediction models to identify novel stromal proteins with a role in BC.
Study Design: 1) Generate proteomic spectra from 300 breast cancers and 300 normal breast specimens using MALDI-TOF MS. 2) Build class prediction models based on these proteomic patterns to identify new proteins with a pathogenic role in breast cancer development. 3) Identify relationships between the proteomic patterns in BC and the critical prognostic factors in BC: lymph node and hormone receptor status. 4) Identification of proteins composing the critical expression signatures using high pressure liquid chromatography (HPLC) and electrospray ionization tandem mass spectrometry (ESI MS/MS).
Relevance: The study of proteomic patterns and identification of novel breast cancer-related proteins should identify new targets for the development of novel strategies for the prevention, diagnosis, treatment and prognostication of breast cancer. This study will elucidate novel proteins which are part of known and unknown regulatory pathways in breast cancer. Since these proteins promote and/or maintain the neoplastic state, they represent an array of tumor specific markers and potentially rational therapeutic targets.
Breast cancer is the most common cancer diagnosed among women and ranks #2 in cancer deaths among women. A small but significant number of men also suffer from breast cancer each year. Given the prevalence as well as the significant morbidity and mortality caused by this disease despite current aggressive therapies, new strategies for diagnosis and treatment of breast cancer are needed. The development of breast cancer from normal breast tissue is the result of progressive accumulation of genetic alterations over time. These genetic changes may result in increased, decreased, or defective protein production. Proteins are the molecules by which genes exert their effects on cells and tissues. The study of protein expression is called proteomics. Proteomic expression patterns in breast cancer are enormously complex. Mass spectrometry is a powerful tool for the rapid and precise identification of proteins, either in an isolated, purified state or in intact tissues. This technology uses a pulsed ultraviolet laser to desorb soluble proteins from tissue, separates them according to their mass-dependent velocities, and displays the detected protein species as a spectrum of mass-to-charge ratios (m/z). This technique permits simultaneous examination of more than 500 proteins within a single tissue specimen. The aim of this project is to characterize the critical differences in protein expression distinguishing breast cancer from normal mammary tissue using mass spectrometry. We expect these studies to identify novel proteins that, in turn, may lead to new strategies for the prevention and treatment of breast cancer.