A PROTEOMIC ANALYSIS OF NEOPLASTIC PROGRESSION IN BREAST CANCER

摘要

The utilization of high-throughput -omics strategies, such as proteomics, in the analysis of breastcancer will function to define central molecular characteristics across a disease that is associatedwith a high degree of molecular heterogeneity. Data reported herein details the investigation ofkey subjects in breast cancer biology focused on the characterization of endogenous andexperimentally-induced disease biology characteristics utilizing the application of LC-MS basedproteomic analyses of both in vitro models of breast cancer as well as primary clinical samples.Results include a combined global and functional proteomic strategy to identify governingfunctional roles for mutually, differentially abundant proteins observed across three divergentcell line models of breast cancer. Further, evidence is presented which provides insights into theregulatory activity of the breast cancer-associated microRNA (miR-145) in several cell linemodels of breast cancer in which expression of this microRNA has been restored. Lastly, robustanalyses are detailed focused on the identification of differential protein characteristics indicativeof disease stage as well as of recurrent disease in breast cancer derived from proteomic analysisof formalin-fixed, paraffin embedded (FFPE) clinical samples. These studies contribute to thefield of proteomics in the form of 1) providing robust experimental workflows directed towardsinvestigation of functional themes and associated functional targets in large protein data sets 2)detailing strategies for navigating the application of proteomic analysis to microRNA targetdiscovery and 3) further development and utilization of methodologies towards the proteomicanalysis of clinical, FFPE tissue samples. Furthermore, these studies benefit the breast cancercommunity on several fronts including 1) the elucidation of provocative protein candidateswhich warrant further investigation for their role in regulating disease mechanisms underlyingvbreast cancer biology and 2) through the discovery of diagnostic markers indicative of discretesubtypes and stages of disease progression in breast cancer. The results reported herein detaildisease-specific protein abundance characteristics associated with neoplastic progression inbreast cancer that will benefit further expansion of the basic biological understanding of thisdisease and describes novel proteins for further evaluation as biomarker candidates for thediagnosis of breast cancer.