Simple SummaryInvasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer and is often detected at an advanced stage. Up to 30% of ILC cases relapse and present a challenge for treatment. Unfortunately, there are few models to study ILC experimentally, which hampers the development of new treatments. To address this challenge, we have created a new ILC in vivo model by grafting triple-negative (TN) human cancer cells into mice. This new xenograft model recapitulates the different stages of ILC and provides a useful tool for researchers performing preclinical studies on TN ILC.AbstractInvasive lobular carcinoma (ILC) is a common breast cancer subtype that is often diagnosed at advanced stages and causes significant morbidity. Late-onset secondary tumor recurrence affects up to 30% of ILC patients, posing a therapeutic challenge if resistance to systemic therapy develops. Nonetheless, there is a lack of preclinical models for ILC, and the current models do not accurately reproduce the complete range of the disease. We created clinically relevant metastatic xenografts to address this gap by grafting the triple-negative IPH-926 cell line into mouse milk ducts. The resulting intraductal xenografts accurately recapitulate lobular carcinoma in situ (LCIS), invasive lobular carcinoma, and metastatic ILC in relevant organs. Using a panel of 15 clinical markers, we characterized the intratumoral heterogeneity of primary and metastatic lesions. Interestingly, intraductal IPH-926 xenografts express low but actionable HER2 and are not dependent on supplementation with the ovarian hormone estradiol for their growth. This model provides a valuable tool to test the efficiency of potential new ILC therapeutics, and it may help detect vulnerabilities within ILC that can be exploited for therapeutic targeting.