Developing and credentialing murine models of ILC

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This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045 and under the parent award R01CA252378 and the Oncology Models Forum. Invasive lobular breast cancer (ILC) is the second most common special histological subtype of breast cancer accounting for up to 40,000 cases yearly 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, being lost at the protein level in over 95% of cases. We recently reported clinical outcomes in >30,000 cases of breast cancer showing that patients with ILC suffer from late recurrences and worse outcome compared to the No Special Type (NST) (1). 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 NST and ILC as a single disease, a problem that has been recognized and voiced by the breast cancer advocate community. ILC is understudied compared to NST, in part due to the limited availability of models and to a paucity of credentialing to identify those that faithfully represent the human disease. As such, it is currently unclear which ILC models are most appropriate to test clinically meaningful questions. Our team is at the forefront of ILC model development with generation and characterization of ILC cell lines, patient-derived organoids (PDO) and patient derived xenografts (PDX). We are committed to continued development, credentialing and sharing of novel models of ILC. As part of the NCI Oncology Models Forum and NCI R01CACA252378 we have developed and characterized ILC cell line models grown in 2D and numerous PDO. In this supplement we will develop and credential novel mouse models of ER+ mammary cancer, studying mice with clinically relevant ILC genetic drivers and transgenic expression of mutant estrogen receptor. We will also develop and credential mouse-derived organoids for sue by other researchers. In this way we aim to accelerate ILC research.