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Abstract P3-02-07: Fatty acid metabolism is associated with chromatin remodeling in mammary epithelial cells

Introduction: Altered metabolism is a hallmark of cancer. We have reported that a set of lipid metabolism (LiMe) genes is over-expressed in the contralateral unaffected breasts (CUBs) of women with unilateral estrogen receptor negative (ER-) breast cancer, who are at high risk for future ER- tumors. We hypothesized that a potential mechanism connecting lipid metabolism to risk of ER- disease may involve epigenetic regulation of gene expression in breast cells by lipids, as shown by McDonnel et. al., Cell reports 2016 in hepatocytes. Methods: Mass spectrometry was performed to profile the composition of lipid species in the sera of patients with ER+ versus ER- disease. MCF-10A cells and mammary organoids from reduction mammoplasty patients were treated with Octanoic (OA) and Linoleic acid (LA) followed by western blot analysis of acetylated histones and sequencing of RNA with qPCR confirmation of significant findings. Partial wave spectroscopic (PWS) microscopy was employed to study change in chromatin. Epithelial RNA from microdissected benign breast samples from CUBs of 84 patients (28 ER+, 28 ER- and 28 healthy controls) were subjected to qPCR. Results: Sera from ER- patients showed higher levels of two triacylglycerides: TAG46:4-FA18:2 (1.25-fold, p=0.05) and TAG 47:2-FA18:2 (1.35-fold, p=0.07), both of which contain LA. MCF10A cells and human mammary organoids showed induction of H3 acetylation at lysine 9 & 14 after treatment with LA and OA treatment at physiological levels. This was accompanied by evidence of chromatin remodeling and 2-fold increase in DNA accessibility on PWS. RNA-Seq of OA treated MCF-10A cells revealed significant upregulation of LiMe genes together with pathways associated with breast malignancy: Notch, Wnt, EMT and adenylate cyclase. The adenylate cyclase pathway (known to be specifically associated with ER- breast cancer risk), was enriched 3.7-fold (p=0.007). In RNA from CUBs of 84 patients, we found overexpression of Notch pathway intermediates that responded to lipid exposure in MCF10A in the ER- group, specifically Notch1 (1.8-fold, p=0.02) and Hey1 (2.9-fold, p=0.05). Conclusion: Specific classes of dietary lipids are the source of acetyl-CoA which acetylates histones and remodels chromatin to modulate gene transcription in ER- MCF10A cells. Thus revved-up fatty acid oxidation may play a role in ER- breast oncogenesis via Notch signaling. Our novel findings point to potential interception strategies that target connections between lipid metabolism and histone modifications. Citation Format: Shivangi Yadav, MiRan Choi, David Van Derway, Greta Braur, Vadim Backman, Seema Ahsan Khan, Susan Clare. Fatty acid metabolism is associated with chromatin remodeling in mammary epithelial cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-07.