Abstract 2213: The normal breast study: Understanding the normal tissue adjacent to breast cancers. Epithelial-to-Mesenchymal transition (EMT) signatures

Significance: Breast Cancers (BC) evolve and acquire adaptive changes while in active communication with the surrounding host normal tissue. Understanding how host tissue interacts with cancers during breast cancer progression could lead to novel biomarkers or targeted therapies. Innovation: We hypothesized that novel molecular subtypes of microenvironment (ME) can be identified and have prognostic value. Stromal signatures are poorly understood and the independent prognostic value of stroma and/or ME response has not been widely studied. Approach: We used gene expression data 1) to identify molecular subtypes of microenvironment, 2) to study the distribution and prevalence of microenvironment subtypes in an ethnically diverse group of BC cases and 3) to test the value of ME in predicting breast cancer progression. In 2009, our team initiated the UNC NORMAL BREAST STUDY (NBS), a unique epidemiologic study of normal tissue from ethnically diverse patients at UNC Hospitals. The NBS has recruited over 200 patients undergoing breast surgery at UNC Hospitals, including cosmetic surgeries, excisional diagnostic breast biopsies, lumpectomies and mastectomies. All participants donate snap frozen and paraffin-embedded normal breast tissue. For all patients who have been diagnosed with breast cancer, the gross distance between the tumor and the normal breast tissue specimen is measured. In addition all study participants are asked to submit a blood sample and complete a telephone interview regarding demographics and environmental exposures. Medical record abstraction is performed to obtain treatment data and anthropometry. Each sample is carefully analyzed for histopathology and whole genome gene expression data is collected. Results: Among the breast cancer patients profiled in our initial studies, unsupervised clustering resulted in two groups of patients, one of which showed expression features suggestive of an activated mesenchyme. We then generated an EMT signature using cell line models and observed that this signature is enriched in one cluster or subgroup of these patients. In the approximately 40% of patients where the EMT signature is enriched, survival was decreased, and survival was significantly decreased among patients with ER positive disease. Conclusion: The NBS allows a unique opportunity to make an impact in discovering novel biology of human breast cancer microenvironment. The information gained from this translational study will establish whether