Abstract 2993: Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast

Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin. It has clinical features distinct from other estrogen receptor-positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. By xenografting lobular cells to the milk ducts, we recapitulate the human disease, including invasion and metastasis to clinically relevant organs. Using patient-derived intraductal xenografts from lobular and non-lobular ER+ HER2- tumors to compare global gene expression we identify extracellular matrix modulation as a lobular carcinoma cell-intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Pharmacological treatment and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC. This is the first study of a hormone-responsive ER+ preclinical lobular model that mimics their clinical counterparts and opens opportunities for the development and evaluation of therapies. Citation Format: George Sflomos , Laura Battista, Patrick Aouad, Fabio De Martino, Valentina Scabia, Athina Stravodimou, Ayyakkannu Ayyanan, Assia Ifticene-Treboux, RLS, Philipp Bucher, Maryse Fiche, Giovanna Ambrosini, Cathrin Brisken. Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2993.