University of Vermont Molecular Characterization Laboratory (Breast)

The Vermont Breast Cancer Molecular Characterization Laboratory will provide the consortium with scientific leadership, technical resources, and access to a large repository of retrospective and prospectively collected breast specimens linked to the rich data of the VBCSS.
1) Identify molecular and cellular signatures in the tumor microenvironment that predict the aggressiveness of early stage screen-detected breast cancers. Increasing evidence suggests that the tumor microenvironment plays an integral role in determining the invasive potential of a primary tumor. We will characterize the cell composition and cell-specific gene expression patterns in the tumor microenvironment of aggressive interval- and symptom-detected breast cancers. We will determine to what extent the presence of these aggressive signatures in early stage screen-detected breast cancers predicts outcomes, using a nested case-control design with data and specimens from the VBCSS. We will also conduct global RNA expression profiling on prospectively collected breast tissue to identify new markers that, in combination with the cellular profiles, will elucidate a comprehensive signature of tumor progression. 2) Lead and participate in collaborative trans-Consortium research projects that produce comprehensive cellular and molecular characterizations of early lesions. Our multidisciplinary research team has extensive experience and a productive track record of consortium-based collaborative research. We envision collaborative trans-network research projects that take advantage of the diversity of expertise, data, and specimens provided by each participating site. In particular, the tumor microenvironment signatures identified in our project may be generalizable across cancers originating in different organs. Likewise, we anticipate that tumor-cell-focused signatures developed by other MCL sites will provide important data and natural opportunities to complement our tumor microenvironment work. 3) Contribute to the Consortiums annotated biospecimen repository of screen-, interval-, and symptom-detected lesions. The depth and breadth of the data and specimens made available through our proposal will enable a wide range of opportunities for the Consortium to address important questions in the characterization of early cancer lesions. The VBCSS has access to archived formalin-fixed specimens for over 10,000 breast cancers and thousands of pre-neoplastic lesions, each annotated with rich longitudinal patient, radiology, pathology, treatment, and outcomes data. Our prospective data collection will enable analyses of fresh and formalin-fixed specimens from newly diagnosed cases.
Advances in breast cancer screening and treatment have reduced breast cancer mortality in the US over the past 30 years. However, the widespread adoption of screening mammography has been accompanied by dramatic increases in early stage breast cancer diagnoses that have not been offset by declines in advanced stage disease. Accumulating evidence suggests that a substantial fraction of screen-detected breast cancers would never have emerged clinically if not detected through screening. While there is extensive debate regarding the magnitude of overdiagnosis, there is widespread consensus that new approaches are urgently needed to distinguish indolent screen-detected cases from those that may be life threatening. The role of the tumor microenvironment in breast cancer progression has been increasingly recognized. Several lines of evidence indicate that breast tumorigenesis is critically influenced by active signaling between malignant breast epithelial cells and non-neoplastic cells of the tumor microenvironment. The goal of our proposal is to identify tumor microenvironment signatures that predict the aggressiveness of early stage, screen-detected breast cancers by minimally invasive methods. We will leverage and refine state-of-the-art technologies to characterize aggressive signatures based on the cellular composition and gene expression of specific cell populations within the tumor microenvironment of interval- and symptom-detected invasive breast cancers. We will then determine whether the presence of these aggressive tumor microenvironment signatures in early stage, screen-detected breast cancer is associated with progression. We will obtain retrospective data on 800 formalin-fixed, paraffin-embedded specimens for analysis from the Vermont Breast Cancer Surveillance System (VBCSS), which has collected integrated patient, radiology, pathology, treatment, and outcomes data on all women undergoing breast imaging in the state of Vermont since 1996. The VBCSS has a large existing repository of over 1,200 centrally-reviewed DCIS specimens and access to over 10,000 invasive breast cancer specimens for cases diagnosed in the state of Vermont. We will also engage in prospective collection of fresh specimens via the Vermont Cancer Center Tissue Biobank, which is also linked to the integrated data of the VBCSS. The identification of aggressive and indolent tumor microenvironment signatures will promote the development of more conservative treatment strategies for the subset of women with favorable prognosis and suggest novel targets for therapeutic intervention in cases with unfavorable prognosis. We have assembled a multidisciplinary research team with nationally recognized expertise in cellular and molecular cancer biology, pathology, cancer screening, and epidemiology, as well as a long track record of productive consortium-based collaborative research. The Vermont Breast Cancer Molecular Characterization Laboratory will provide the consortium with scientific leadership, technical resources, and access to a large repository of retrospective and prospectively collected breast specimens linked to the rich data of the VBCSS.