Abstract 1365: Histamine from mast cells protects against breast cancer recurrence

Abstract One in eight women will develop breast cancer in their lifetime. 20-30% of these women develop recurrent metastatic disease, for which clinical treatments have limited efficacy. Metastasis is thought to be a stepwise process, terminating with extravasation into distal tissues. After this distal extravasation, cancer cells do not always immediately proliferate, but remain dormant. These dormant cells may awaken through yet-unknown mechanisms. There is therefore an urgent need to better understand dormancy and reawakening to mitigate the risk of metastatic recurrence. Previous work from our group has shown that elevated circulating cholesterol, and particularly an oxidized metabolite 27-hydroxycholesterol (27HC), has a pro-metastatic effect with breast cancer. Bacon is a high cholesterol food that is often prepared in a highly oxidative pan-frying process. Using mouse models, we demonstrate that consumption of cured, fried bacon promotes metastatic recurrence from dormancy. Assessment of metastatic tissues showed that consumption of cured fried bacon fat dramatically reduced mast cell (MC) numbers. MCs are granulocytic innate immune cells whose function in reemergence from dormancy is not well characterized. Interestingly, depletion of mast cells also stimulated reemergence, suggesting that mast cells might be protective against cancer progression. A major mediator of MC function is histamine. Therefore, we used small molecules to test the effects of histamine. Importantly, histamine 2 receptor antagonism stimulates recurrence. RNA-Sequencing data revealed that H2-receptor antagonism yields a unique transcriptional profile enriched with genes associated with platelet activation. Subsequent work indicates that H2 antagonism primes platelets towards activation which then increases neutrophil NETosis. Thus, we establish a novel metastatic axis: Diet - Mast cell - H2-receptor - Dormancy. The ultimate goal is to leverage this axis to develop novel therapeutic targets or lifestyle interventions to prevent recurrence. This work was supported by the American Institute for Cancer Research grant (713063), the National Cancer Institute (R01CA234025) and Department of Defense Breast Cancer Research Program Era of Hope Scholar Award (BC200206). Further support awarded to CPS from the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number T32EB019944 and ATN from a National Institutes of Environment Health Sciences and Research Training in Toxicology and Environmental Health (T32) Fellowship (ES007326). Citation Format: Claire P. Schane, Adam T. Nelczyk, Cheng Chen, Shruti V. Bendre, Erin Weisser, Hashni E. Gamage, Mohammed Kadiri, Michael T. McHenry, Jiyoung Seo, Yu Wang, Natalia Krawczynska, Dhanya Pradeep, Lara I. Kockaya, Yifan Fei, Shin-Hsuan Hsiao, Nicki J. Engeseth, Michael K. Wendt, Timothy M. Fan, William G. Helferich, Erik R. Nelson. Histamine from mast cells protects against breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1365.