Although European-American (EA) women, overall, have higher breast cancer incidence than African- American (AA) women, AA women are more likely to be diagnosed at a younger age and to have more aggressive tumors, characterized by higher grade, higher proliferative indices, and lack of expression of estrogen (ER) and progesterone receptors (PR). AA women are also more likely than EAs to have triple- negative breast cancers (TNBCs), which are negative for ER, PR and HER2. These tumors have poor prognosis because they tend to be higher grade and are not responsive to anti-estrogen or anti-HER2 therapy, thus with fewer treatment options available. The reasons for these racial disparities in breast cancer aggressiveness and age at onset are unknown. The Hippo pathway was first identified in Drosophila for its control of organ size by modulating cell growth, proliferation and apoptosis, with all the core components well conserved in mammals. Down-regulation of Hippo pathway components LATS1/2 by DNA hypermethylation has been associated with large tumor size, lymph node metastasis and ER/PR negativity. Our preliminary data also showed that dysfunction of Hippo pathway components YAP/TAZ activates the EGFR signaling and YAP/TAZ is specifically increased in triple-negative and high-grade breast tumors, the subtypes more prevalent among young AA than EA women. Based on the above evidence, we hypothesize that dysfunction of the Hippo signaling pathway leads to aberrant activation of EGFR signaling in the more aggressive breast cancer, which occurs more frequently in AA than EA women. We will investigate this hypothesis in the context of two existing study populations, with the following two specific aims: 1) Determine whether YAP/TAZ-activated EGFR signaling pathway contributes to TNBC tumorigenesis, and 2) Investigate differential EGFR activation by YAP/TAZ between AA and EA women using breast cancer tumor collections. The approach is innovative, because it takes new basic science discoveries to human populations and investigates heretofore unexamined pathways in relation to breast cancer disparities. The proposed research is significant, because it is the first step in a translational continuum of research that is expected to lead to discovery of the role of the Hippo signaling pathway alterations in AA and EA women, as well as associations with aggressive breast cancer. This translational work will ultimately help identify women at a high risk of aggressive breast cancers and discover novel approaches to eliminate breast cancer racial disparities. Our integral approach may also be applied to studying other molecular pathways relevant to health disparities on a broader scale.