Abstract P6-11-02: Mitochondria-Nuclear Crosstalk Regulates the WNT Pathway in Triple-Negative Breast Cancer

Abstract

Abstract Compared to hormone receptor (HR) positive breast cancer (BC), basal or triple-negative BC (TNBC) suffers a poor prognosis caused by a limited understanding of its driver signaling pathways. We used the transmitochondrial cybrid approach to understand the metabolic reprogramming and mitochondria-nuclear crosstalk in metastatic TNBC. In cybrids, mitochondria from cancer and benign cells are compared under a commonly defined nuclear background. Using cybrid-based discovery and its validation in cell lines, patient-derived xenografts, and clinical data, we have previously reported the activation of fatty acid oxidation (FAO) in metastatic TNBC. Recently, we developed a unique gene (DEG) signature by integrating gene expression data from cybrids with different omnibus databases such as TCGA and METABRIC. Our DEG could effectively distinguish the PAM50 subtypes of BC. Further analyses nominated negative regulation of the canonical WNT signaling pathway as one of the major pathways altered by mitochondrial character. The WNT pathway is known to regulate cell signaling, metabolism, epithelial-mesenchymal transition (EMT), and cancer stemness. Cybrids with benign mitochondria showed transcriptional activation of negative WNT regulators, including DKK1, SOST, DAB2, and CAV1. Citrate is a key metabolite from the tricarboxylic acid cycle (TCA cycle) and is an intermediate of many other metabolic pathways. Analysis of TNBC cybrids, cell lines, and BC tissues suggest that in TNBC, citrate levels are increased with the activation of CPT1A, the rate-limiting enzyme of FAO. We confirmed the reduction of the beta-catenin protein in TNBC cells after pharmacological and genetic inhibition of CPT1A and mitochondrial citrate transporter (SLC25A1). We further analyzed the gene set enrichment analysis (GSEA) using gene expression data developed from short and long-term CPT1A inhibited TNBC cells and observed that the FAO alters polycomb repressive complex 2 (PRC2) activity. PRC2 is a critical modulator of the H3K27 methylation pattern as well as pathways related to cancer stemness, including WNT/beta-catenin and Hedgehog (SHH) pathways. These results suggest that the mitochondrial FAO transcriptionally inhibits WNT antagonist genes through repressive histone modification and consequently activates the canonical WNT pathway and cancer stemness. Overall, our current observations provide new insights into the regulation WNT pathway by mitochondria-nuclear crosstalk in TNBC. Citation Format: Sukjin Yang, Jun Hyoung Park, Suna Kim, Meron Ghidey, Benny Kaipparettu. Mitochondria-Nuclear Crosstalk Regulates the WNT Pathway in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-02.