Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after the more common invasive ductal breast cancer (IDC). In 2020, ILC will affect up to 40,000 patients in the US, and if considered an independent malignancy is the 6th most frequent cancer in women. Loss of E-cadherin (CDH1) is the pathognomonic feature of ILC, which leads to a single-file pattern infiltration of small discohesive cells into the stroma. Patients with ILC suffer from late recurrences and metastasis to unique sites such as the urogenital tract (e.g. ovary) and the gastrointestinal (GI) tract (e.g. peritoneum). Despite numerous studies showing unique clinical, histopathological, and molecular features of ILC, clinical trials and guidelines mostly ignore the unique aspects of ILC, and treat IDC and ILC as a single disease. 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. ILC is currently understudied at least in part due to a lack of credentialed models and it is currently unclear which ILC models are most appropriate to test clinically meaningful questions. We will collaborate with the Cancer Dependency Map Project (DepMap - CCLE) and members of PDXNet to comprehensively credential ILC models. We have established a team with complementary expertise in ILC biology, rodent modeling, bioinformatics, immunology, pathology, medical oncology, and breast cancer advocacy and will use innovative validation strategies to cross-compare in vitro and in vivo translational ILC models. Our goal is to create a robust set of well-curated models that are credentialed to provide translationally reliable information for evaluating targeted therapies in primary and metastatic ILC. In Aim 1 we will molecularly characterize ILC models and compare them to human ILC. This will include 19 ILC or ‘ILC-like’ cell lines, 20 primary ILC organoids, 8 patient derived xenografts, 2 homograft rodent models and 3 genetically engineered mouse models (GEMM). We will assess histopathology and perform comprehensive genomic, epigenomic and transcriptomic analyses. In Aim 2 we will focus on in vitro growth phenotypes and in vivo metastasis to determine which models recapitulate the unique growth pattern seen in human ILC. Since we have recently sequenced unique sites of ILC metastasis (ovary, GI) in the human disease, we will compare the molecular profile of our metastasis models to human ILC metastasis. Finally, Aim 3 will focus on therapeutic efficacy. We will work with the Broad Institute to perform CRISPR and drug screening on ILC cell lines and organoids and make all data available in the DepMap portal. In vivo we will assess endocrine therapy response in homografts and compare the results to an ongoing ILC clinical trial led by our group. We will also characterize the immune cell infiltrate and response to checkpoint inhibitors in homograft rodent ILC model...