Development of novel early detection and stratification markers for breast cancer: integrating pathology and proteomics

Our limited understanding of the biological impact of the whole spectrum of early breast lesions together with a lack of accurate molecular-based risk criteria for the diagnosis and assignment of prognostic significance to biopsy findings presents an important problem in the clinical management of patients harboring precancerous breast lesions. As a result, there is a need to identify biomarkers that can better determine the outcome of early breast lesions by identifying subpopulations of cells in breast premalignant disease that are at high-risk of progression to invasive disease. A first step towards achieving this goal will be to define the molecular phenotypes of the various cell types and precursors - generated by the stem cell hierarchy - that are present in normal, benign, and malignant conditions of the breast. For the past years our laboratory has carried out a systematic and comprehensive proteomic profiling of normal and malignant breast tissue in high-risk patients in a search for differentially expressed markers for early detection and stratification of patients, as well as novel targets for therapeutic intervention in breast cancer. This lecture will describe our efforts to address some of the issues that clinical proteomics is faced with, partly due to the formidable heterogeneity of tumors, but also due to limitations of the current proteomic technologies. The examples presented will include results from our work to identify proteins that characterize specific steps in the progression from early benign lesions to malignancy in breast apocrine carcinoma, the creation of a comprehensive database of proteins secreted/shedded by tumor cells and present in tissue interstitial fluid and from a systematic proteomic study to characterize the phenotypes of the different cell subpopulations present in normal human mammary tissue that can help define the molecular phenotypes underlying mammary epithelial normalcy. Finally results from our recent work on therapy-relevant stratification of triple negative breast cancer patients will also be discussed.