~30,000 new cases of invasive lobular breast cancer (ILC) diagnosed per year make ILC the 6th most common cancer in women. ILC is treated almost identically to the more common invasive ductal cancer (IDC), despite differences in clinical presentation and tumor biology, including the near universal loss of E-cadherin. Although ILCs show better prognostic markers than IDC, such as high rates of estrogen receptor (ER) positivity and low proliferation, patients with ILC often develop resistance to endocrine therapy and in the long term suffer more recurrences than IDC. Our long-term goal is to improve outcome for patients with ILC, a disease associated with limited understanding and representing a great unmet clinical need. To understand mechanisms driving ILC endocrine resistance, we developed endocrine-resistant ILC cell line models, and collected endocrine resistant metastatic breast cancer samples, and unbiased transcriptomic profiling led to the identification of fibroblast growth factor receptor 4 (FGFR4) as the most overexpressed gene. Analysis of publicly available databases lead to identification of hotspot FGFR4 mutations. Lack of consistent overexpression of FGFR1-3 in endocrine resistant models and metastatic tissues strongly suggests a unique and previously unappreciated role for FGFR4 that warrants further study. While FGFR4 overexpression and mutations are observed in both IDC and ILC, they are significantly enriched in ILC. This suggests that the unique genetic background of ILC, including the well-known loss of E-cadherin but also the more recently identified activation of ERBB2/ERBB3, may provide a permissive environment for FGFR4 signaling. Functionally, FGFR4 loss or inhibition results in altered expression of ER target genes and decreased growth and colony formation. Finally, preliminary studies of combined FGFR4 and ER targeting confer synergistic growth inhibition. We therefore hypothesize that the unique genetic background of ILC creates a permissive environment for FGFR4 signaling to mediate endocrine resistance, and that the combination of FGFR4 inhibition and endocrine therapy represents a novel treatment strategy. In the current study, we will i) determine how FGFR4 causes endocrine resistance in breast cancer, and ii) examine whether key genomic features of primary and metastatic breast cancer cross-talk and enhance FGFR4 signaling and activity, and iii) credential FGFR4 as a druggable target in breast cancer therapy by defining biomarkers. Our collaborative team with expertise in molecular biology, biostatistics/bioinformatics, pathology and medical oncology will utilize unique models, valuable clinical samples, promising drugs that are already in trials, and innovative approaches and tools to test our focused hypotheses on a novel role of FGFR4 in endocrine resistance. We expect to gain fundamental knowledge of how the readily druggable ER-FGFR4 axis signals in ILC and!to assess FGFR4 inhibition as a novel treatment strategy in endocrine resistant breast cancers. !