Abstract P5-01-21: Epigenetic changes induced by combinatorial pterostilbene and resveratrol in Her2-positive and triple-negative mammary cancer via gut microbiome-metabolome axis modulation

Abstract With evolution of chemotherapy, the mortalities associated with the two most aggressive breast cancer subtypes, Her2 overexpressing and triple-negative breast cancers (TNBC), have significantly declined. The natural phytoalexins pterostilbene and resveratrol, extracted from grapes and berries, showed promising effects in inducing apoptosis and cell cycle arrest in human TNBC cell lines when administered singly and in combination, with minimal toxicity towards non-malignant cells. The primary goal of this study was to evaluate the effectivity of the phytochemicals in vivo considering the interference by tumor microenvironment, immune cells, bioavailability of the phytochemical, differential metabolism, and varied gut microbial composition. After administering a long regime of dietary intervention of the phytoalexins in transgenic mice models, we observed a delayed occurrence of mammary neoplasms with a significant decrease in progression of tumor volume and weight in treatment groups vs. the control group. The group of subjects treated with combination of 3:1 (w/w) pterostilbene and resveratrol demonstrated synergistic effects in impeding the mammary cancer phenotype. Concurrently, we discovered that these treatments increase the abundance of specifically Firmicutes phyla of bacteria which indicates recuperation from diseased condition. Simultaneous evaluation of plasma short chain fatty acid indicates an increase in butyric acid levels in pterostilbene high group and decrease in caproic acid. Our findings also reveal notable differences in expression of tumor suppressor genes associated with Her2 (Erbb2) signaling pathway such as p53, PTEN, p21 and oncogenes such as Her2/neu, Ras, Bcl2 and Myc. We also found significant changes in the expression of epigenetic modulators such as histone deacetylases (HDACs), histone demethylases (KDMs) and DNA methyltransferases (DNMTs). Overall, our results demonstrate efficacious in vivo application of combinatorial pterostilbene and resveratrol in prevention of aggressive hormone response-negative breast cancer via the modulation of gut microbiome and metabolome and suggests possible epigenetic mechanisms associated with anticancer gene regulation. Citation Format: Sebanti Ganguly, Trygve O. Tollefsbol. Epigenetic changes induced by combinatorial pterostilbene and resveratrol in Her2-positive and triple-negative mammary cancer via gut microbiome-metabolome axis modulation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-01-21.