Targeting the Prometastatic Microenvironment of the Involuting Mammary Gland

: We hypothesized that Latent TGFbeta Binding Protein 1 (LTBP1) expression creates a pro-metastatic environment. We proposed three aims to test this hypothesis 1) Determine the utility of LTBP1 expression as a biomarker in human breast cancer 2) Determine the consequences of modulating LTBP1 levels on cell motility, invasion and metastasis in human and murine breast cell lines 3) Investigate the pathological significance of gain and loss of LTBP1 in genetically engineered mouse models. Our most important findings in this cycle are that LTBP1 expression is robustly elevated during involution, a window of development associated with heightened risk of highly metastatic breast cancer, that high LTBP1 expression occurs in luminal HER2-positive and basal breast cancers and expression level within these subgroups correlates with poor outcome. This was achieved by determining the expression pattern of LTBP1 in LTBP1-lacZ reporter mice, by qPCR and immunofluorescence over the entire course of mammary development in mice and by bioinformatically mining databases of human breast cancer. During this period we have also validated antibodies, screened breast cancer lines for LTBP1 expression and developed lentiviral expression tools that will enable us to proceed to test the effects of modulating LTBP levels on cell migration.