Invasive lobular breast carcinoma (ILC) is the most common special histological subtype of breast cancer, accounting for 10-15% of all cases, and characterized by the loss of adherens junctions through inactivating mutations in E-cadherin. Although currently existing genetically engineered mouse models of ILC faithfully capture its dyscohesive, single-file growth and expression of estrogen receptor alpha (ER), they do not fully recapitulate all aspects of human ILC such as unique sites of metastases and endocrine response. While recent work on human ILC cell lines has proven them useful for studying ILC in vitro, there is limited data on their growth as xenografts in mice and their fidelity as in vivo models. Using dual bioluminescent and fluorescent labeled ER-positive human ILC cell lines (MDA-MB-134, SUM44PE, MDA-MB-330, BCK4), herein we characterized their growth orthotopically and at secondary sites following spontaneous or experimental metastasis. Mammary fat pad xenografts gave rise to primary tumors with single-file infiltration and cytoplasmic translocation of p120-catenin, characteristic of human ILC. The tumor microenvironment exhibited deposition of collagen fibers and infiltration by fibroblasts and neutrophils. In this orthotopic model, we observed spontaneous metastases of most cell lines to bones, brain and ovaries, closely mirroring the clinical patterns of human ILC dissemination. In contrast, experimental metastases were only observed following intravenous or intracardiac xenografts of MDA-MB-134 cells. Interestingly, tail vein injections of this cell line lead to colonization of bones and lymph nodes but not of lungs, while intracardiac injections resulted in brain, bone and lymph node metastases. Importantly, we observed high ER expression in the primary tumors and the metastatic lesions, along with a significant response to the selective ER down-regulator fulvestrant in both the mammary fat pad and intracardiac models. Ongoing work focused on genomic and transcriptional analyses of primary tumors and metastases, as well as of cell lines isolated from these lesions, will reveal additional mechanistic insights into the biology of ILC dissemination. This is the first report of ER-positive and endocrine responsive human cell line xenografts faithfully representing unique ILC features such as ovarian metastases. These versatile models will serve as an invaluable pre-clinical platform for validating candidate ILC genetic drivers and testing novel therapeutics towards translation into the clinic.
Citation Format: Nilgun Tasdemir, Laura Savariau, Julie Scott, Joseph D. Latoche, Weizhou Hou, Kyle Biery, Minji Chung, Emily A. Bossart, Sreeja Sreekumar, Daniel D. Brown, Azadeh Nasrazadani, Ye Qin, Jagmohan Hooda, Fangyuan Chen, Carlos A. Castro, Carolyn J. Anderson, Jennifer Atkinson, Peter C. Lucas, Nancy E. Davison, Adrian V. Lee, Steffi Oesterreich. ER alpha-positive human cell line xenograft models recapitulate metastatic dissemination and endocrine response of invasive lobular breast carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-002.