Abstract 1270: ECHS1 mediates metabolic disruption in hormone receptor-positive breast tumor microenvironment

Abstract

Unchecked hyperadiposity causes systemic metabolic perturbations and subclinical chronic inflammation, promoting hormone receptor positive (HR+) breast cancer. Murine models of high-fat diet-induced obesity have shown alterations in proteins involved in fatty acid binding and mitochondrial beta-oxidation, including enoyl-CoA hydratase short chain 1 (ECHS1), which promote increased uptake of fatty acids by primary tumor cells. This creates a metabolic tug of war between tumor and immune cells in the tumor microenvironment, thereby depriving cytotoxic immune cells of the metabolic reprogramming for anti-tumor functionality. Nonetheless, metabolic gene expression changes in breast tumor microenvironment of obese individuals remain elusive. We hypothesize that increased expression of ECHS1 leads to immune dysregulation in breast tumor microenvironment and increases risk of cancer progression. Proteomic and genomic expression and survival characteristics of ECHS1 in invasive breast cancer was explored in The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium. We the modeled the effects of ECHS1 expression on immune infiltration in the tumor microenvironment using a regression framework. We also performed single cell RNA sequencing analysis for differential expression of ECHS1 in various human breast cells. Additionally, expression level of ECHS1 was validated in silico in adipose tissue to elucidate increased immune dysregulation and risk of progression of breast carcinoma in obese individuals. We found a significantly increased expression of ECHS1 at both RNA and protein levels in HR+ breast cancer (p<0.001 for both), compared to Herceptin 2 receptor-positive or triple negative breast cancer. High expression of ECHS1 in female breast cancer is also associated with significantly decreased survival based on the TCGA data. Further, we found a significantly negative correlation of CD8+ T cells, neutrophils, and macrophages, and a significantly positive correlation of regulatory T cells with ECHS1 expression in the breast tumor microenvironment. We discovered increased expression of ECHS1 in luminal epithelial cells compared to myoepithelial cells based on single cell RNA sequencing. Lastly, high expression of ECHS1 protein expression based on immunohistochemistry was confirmed in human adipocytes. Collectively, our observations support the hypothesis that preferential uptake of free fatty acid through increased expression of ECHS1 in HR+ breast cancer impairs cytotoxic and anti-tumor effects of CD8+ T cells in the tumor microenvironment. Immune dysregulation is further amplified in obese individuals given increased levels of adipose cells and higher ECHS1 expression. Altogether, ECHS1 is a putative biomarker and potential therapeutic target as its downregulation may improve survival in obese patients with HR+ breast cancer. Citation Format: Tina Bharani, Divyansh Agarwal, Estefania Roldan-Vasquez, Jessalyn Ubellacker, Ted A. James. ECHS1 mediates metabolic disruption in hormone receptor-positive breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1270.