Intraductal Xenografts Model Lobular Carcinoma of the Breast and Reveal Matrix Remodeling by LOXL1 as a Targetable Hallmark II

Invasive lobular carcinoma (ILC) is the most frequent specific histological subtype of breast cancer (BC). It has distinct clinical features from other estrogen receptor positive (ER+) BCs but the molecular mechanisms underlying the characteristic biology are unclear because we lack experimental models to study it. Here, we generate xenograft models with ILC-derived SUM-44 PE and MDA-MB-134-VI cells by grafting them to mouse milk ducts that recapitulate the human disease including metastasis to visceral organs. Transcriptomic analysis of intraductal ER+ PDXs reveals extracellular matrix modulation as an ILC-specific trait. This signature confirms in patient datasets. The collagen modifying enzyme LOXL1 is overexpressed specifically in ILCs by tumor cells; treatment with a LOX inhibitor, BAPN, and LOXL1 silencing decrease tumor growth and inhibit metastasis by disrupting ECM structure/fibrils with down modulation of ER, IGFR, and FGFR signaling. Hence inhibition of LOXL1 is a promising therapeutic strategy for ILC. Expression profile of 6 FACS sorting RFP+ SUM44 intraductally xenografted mammary glands treated with PBS or BAPN