Abstract
Abstract Disclosure: C.P. Schane: None. A. Nelczyk: None. C. Chen: None. H. Vidana Gamage: None. M. Kadiri: None. M.T. McHenry: None. S. Bendre: None. N. Krawczynska: None. M.A. Henn: None. D.C. Castro: None. J. Chen: None. R.I. Tejeda: None. S. Hsiao: None. N.J. Engeseth: None. J.V. Sweedler: None. M.K. Wendt: None. T. Fan: None. W.G. Helferich: None. E.R. Nelson: None. One in eight women will develop breast cancer in her lifetime, with metastasis being the leading cause of mortality. Once the cells colonize the metastatic site, they do not always immediately begin to proliferate, but remain dormant. These dormant cells reside in the tissue, until mechanisms, which remain unknown, awaken the dormant cells and they resume malignant proliferation. Due to the large and growing population of breast cancer survivors at risk of metastatic recurrence, there is an urgent need to elucidate the mechanisms of dormancy and develop therapeutics to prevent reemergence. Elevated levels of circulating cholesterol are a risk factor for breast cancer recurrence. Preclinical work has demonstrated that oxysterol cholesterol metabolites such as 27-hydroxycholesterol (27HC) can promote tumor metastasis. Here, we show that exogenous 27HC lead to a more rapid reemergence from dormancy, using the syngeneic mouse D2.0R model of mammary cancer dormancy. Since it would be expected that cooking high cholesterol foods, such as bacon, under oxidative conditions, such as pan-frying, would produce fat containing cancer-promoting cholesterol metabolites, we hypothesized that consumption of such cooked foods would also promote reemergence from dormancy. Interestingly, consumption of cured, fried bacon fat (cfBF), but not uncured fried bacon fat (ufBF) resulted in reemergence. When metastatic tissues were assessed, it was found that consumption of cfBF dramatically reduced mast cell numbers. Since mast cells (MC) are major contributors to local histamine production, we next tested whether various anti-histamines could alter dormancy. This led to the striking finding that H2 antagonists promoted the breaking of dormancy. Our ongoing work is aimed at further elucidating this novel metastatic axis: Diet - MC - H2 - Dormancy, with the ultimate goal of leveraging it to develop novel therapeutic targets or lifestyle interventions. Therefore, our results are expected to provide the foundation for dietary and medical approaches to reduce the risk of recurrence among breast cancer survivors. 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 ATN from a National Institutes of Environment Health Sciences and Research Training in Toxicology and Environmental Health (T32) Fellowship (ES007326). Presentation: Thursday, June 15, 2023
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