Background: Incidence of breast cancer brain metastases (BCBM) is on the rise due to improved management of systemic disease and ranges from 15-20% in women with disseminated breast cancer. Common chemotherapeutic strategies have limited efficacy for brain metastases due to the presence of the blood brain barrier (BBB). Prevention of metastasis after diagnosis of primary breast tumors may lead to new treatment strategies. TGF-ß is a biomolecule in the metastatic pathway and inhibition of its expression can be achieved by treatment with the antihypertensive agent Losartan. Herein we hypothesized that treatment with Losartan will decrease metastatic burden and improve survival in a preclinical model BCBM.
Methods: Athymic female nude mice were separated into four groups as follows: Vehicle, (saline, 50µL/day), SB431542 (Inhibitor, 5mg/kg/day), Low Dose Losartan (10mg/kg/day) and High Dose Losartan (25mg/kg/day). On day 7 mice were intracardially injected with 175,000 cells of either JIMT-1-Br-LUC-GFP (HER2+) or MDA-MB-231Br-LUC (TNBC) breast cancer cell lines. Tumor burden was monitored once weekly utilizing bioluminescent imaging. Mice were allowed to progress until neurological symptoms arose. Following euthanasia, brains were extracted, sectioned and analyzed to determine number of metastatic lesions and size.
Results: With regard to survival, no significance was shown in the JIMT-1 (HER2+) metastatic model. The MDA-MB-231Br (TNBC) model demonstrated an increase in survival in all treatment groups compared to vehicle. End time-point analyses showed no difference in metastases number in either model, however, the low dose treatment group in the MDA-MB-231Br model had a smaller brain burden of metastases than high dose treatment as well as inhibitor treatment.
Conclusions: Losartan reduced metastatic seeding in the MDA-MB-231Br (TNBC) brain metastasis model, but had little to no effect in the JIMT-1 (HER2+) model.
Citation Format: Mark V. Pinti. TGF-ß inhibition as a novel strategy to prevent breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1263.