Abstract PD7-02: Novel human cell line xenograft models of ERα-positive metastatic invasive lobular breast carcinoma as pre-clinical platforms for validating candidate genetic drivers
Authors: Tasdemir N , Scott J , Laotche J , Hou W , Bossart EA , Atkinson J , Sflomos G , Sreekumar S , Castro C , Anderson C , Lee AV , Brisken C , Lucas PC , Davidson NE , Oesterreich S 
Published: May 2019

Invasive lobular breast carcinoma (ILC) is the second most common subtype of breast cancer following invasive ductal breast carcinoma, accounting for 10-15% of all cases. Despite the intriguing histological and clinical differences between these two subtypes, ILC has been chronically understudied. Human ILC cell lines and xenografts are regarded to be of limited utility for ILC research due to slow proliferation rates in culture and low reported intake rates. Data on human ILC cell line xenografts remains limited and knowledge of their metastatic capacity is currently lacking. Using Estrogen Receptor alpha (ER)-positive human ILC cell lines labeled with dual bioluminescent and fluorescent reporters, herein we performed a comprehensive in vivo characterization of their growth as primary tumors orthotopically in the mammary fat pad, as well as at secondary sites following spontaneous or experimental metastasis. Primary tumors exhibited the characteristic dyscohesive, single-file growth of ILC cells, faithfully recapitulating the histology of human ILC tumors. In vivo bioluminescence imaging coupled with ex vivo fluorescence analysis revealed spontaneous metastases to the bone, brain, lungs and ovaries, closely mirroring the clinical patterns of ILC tumor dissemination. This was in stark contrast to experimental metastasis, where none of the cell lines colonized the lungs when injected into the tail vein and bone colonization was observed with only one cell line following intracardiac injections. The metastatic lesions harbored the classical histological features of ILC, including single strand growth, loss of E-cadherin-mediated adherens junctions and mislocalization of p120-catenin to the cytoplasm. Importantly, both the primary tumors and the metastases exhibited high ER expression and significant response to the anti-endocrine agent fulvestrant - a selective ER downregulator. Using these models, we will also present data from functional studies validating candidate genetic drivers of ILC disease progression, which are associated with poor recurrence-free survival in patients with ILC. Ongoing work focused on genomic and transcriptional analyses of metastatic lesions and isolated cell lines from these models will pinpoint additional candidate drivers of ILC dissemination. This is the first report of a hormone responsive ER+ metastatic xenograft model faithfully representing unique ILC features such as ovarian metastases, which will serve as a valuable pre-clinical platform for testing novel therapeutics towards translation into the clinic.

Citation Format: Tasdemir N, Scott J, Laotche J, Hou W, Bossart EA, Atkinson J, Sflomos G, Sreekumar S, Castro C, Anderson C, Lee AV, Brisken C, Lucas PC, Davidson NE, Oesterreich S. Novel human cell line xenograft models of ERα-positive metastatic invasive lobular breast carcinoma as pre-clinical platforms for validating candidate genetic drivers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-02.