Breast cancer (BrCa) is the second most prevalent cancer (other than skin cancer) and the second most common cause of cancer-related death after lung cancer for women in the United States. BrCa is a not a single disease, but rather a complex and heterogeneous group of diseases with different molecular alterations. The activation status of the Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal growth factor Receptor-like 2 (HER2) are the main diagnostic and prognostic factors and dictate treatment selection. Unfortunately, some tumors ascribed to the same ER/PR/HER2 subtype will respond to treatment while others will not. This indicates that key undetected genetic and epigenetic differ-ences exist and likely contribute to the high variability of treatment response. Thus, there is an urgent need to identify informative molecular biomarkers that can serve to better manage the individual needs of each patient and guide treatment selection. This proposal focuses on the clinical application of microRNAs (miR- NAs) as a novel class of biomarkers for BrCa management. MiRNAs are short non-coding RNA genes that act as post-transcriptional regulators of gene expression. Altered expression of specific subsets of miRNAs has been linked to different types of hematologic and solid tumors, and, consequently, miRNAs are being regarded as promising biomarkers for early detection, diagnosis and/or prognosis. We and others have linked a small subset of miRNAs to BrCa using whole breast tissue biopsies as RNA source for expression profiling analysis. Independently, in vitro studies have revealed mechanistic interactions between miRNAs and protein-encoding genes with clinical implications in BrCa;notably, specific miRNAs have been involved in the modulation of ER and HER2 signaling. Since most diagnostic and prognostic assessment for BrCa are conducted on formalin-fixed paraffin-embedded tissue sections using morphology-based assays, we have recently implemented a sensitive fluorescence-based method that will enable us to co-detect miRNA expression by in situ hybridization (ISH) and protein expression by immunohistochemistry (IHC) in the same tissue section for cell type co-localization and functional studies. Here, we propose to use this combined ISH/IHC assay: i) To determine miRNA expression in tissue microarrays which were designed by NCI Co-operative Breast Cancer Tissue Resources (CBCTR) to find marker associations with disease progression and disease outcome;ii) To validate identified miRNA signatures in an independent cohort of patients from our institution;iii) To assess the potential utility of identified signatures to predict treatment response in dif- ferent adjuvant therapy settings using recurrence-free survival as endpoint marker and in a neoadjuvant therapy setting using pathological complete response as endpoint marker.

Public Health Relevance

MicroRNAs are a recently-discovered class of short non-coding RNA genes that rapidly emerged as a new paradigm in the field of cancer biology. In this proposal, we will investigate the clinical utility of microRNAs as indicators for risk assessment of disease progression and outcome, and predictors of treatment response. For these studies, we will use a quick and sensitive fluorescence-based method, which is fully compatible with automated clinical immunohistochemistry assays. We expect to generate important new information that could have a high impact with respect to management of breast cancer. Our results should provide a solid foundation to develop miRNA-based clinical assays to assist physicians in making crucial decisions with regards to treatment of patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Biomarkers Study Section (CBSS)
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Lively, Tracy (LUGO)
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Dartmouth College
Internal Medicine/Medicine
Schools of Medicine
United States
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