Abstract 6934: Acetate-induced transcriptomic alterations reveal potential therapeutic targets in triple negative breast cancer
Authors: Gabriel Borges-Velez, Diego N. Bracero-Sánchez, Liah M. Román-Calderón, Oscar A. Loperena-González, Ariana S. García-Lopez, Angel J. Amaral-Maisonet, Jeannette L. Salgado-Montilla, Esther A. Peterson-Peguero, Josue Perez-Santiago
Journal: Cancer Research (2025)

Abstract Background: Triple Negative Breast Cancer (TNBC) is the most aggressive subtype of breast cancer and lacks effective therapies. The MDA-MB-231 cell line, derived from TNBC, is used to evaluate new therapeutic strategies. Acetate, a microbial short-chain fatty acid (SCFA), is a key source of acetyl-CoA during metabolic stress and plays a critical role in regulating cancer cell epigenetics and transcriptomics. Acetate’s signaling functions may be a significant factor in cancer growth and progression, however the role of acetate in TNBC remains unclear. Here, we evaluated the effects of acetate on the gene expression of TNBC cells. Methods: We used MDA-MB-231 as our cell model for TNBC. Cells were then exposed with sodium acetate at a concentration of 5mM or growth media (negative control) for 24 hours in triplicates. After exposure, total RNA was extracted (Qiagen RNAeasy Mini kit) and sequenced using the Illumina NextSeq (2 X 75bp). The higher-quality reads were aligned, annotated, and quantified to the human genome (hg38) using STAR and RSEM softwares. Gene expression analysis was performed in R statistical software (packages tximport and DESeq2) and genes with an adjusted p-value &amp;lt; 0.05 were considered significant. Functional and enrichment analyses were performed using Metascape (FDR p&amp;lt;0.05). Results: There were 1410 differentially expressed genes associated with acetate treatment. Adenylosuccinate lyase (A0A1W2PRX2), a novel described protein, was the highest upregulated gene (log2 fold change: 8.25), while dorsal inhibitory axon guidance protein (DRAXIN) was the most downregulated gene (log2 fold change: -2.70). In addition, there was a significant increase in the levels of kinesin family member 12 (KIF12) and protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B), which have been associated with chemoresistance. Significantly impacted biological processes and pathways include regulation of cell projection organization, response to hormone, chromatin remodeling, cytokine signaling in immune system, signaling by receptor tyrosine kinases, epithelial cell differentiation, response to oxidative stress, and DNA damage response. Conclusion: Acetate can promote TNBC cell growth and disease progression via inflammatory mechanisms and lipid metabolism. The observed increase and decrease in A0A1W2PRX2 in DRAXIN expression, respectively, highlight these genes as potential novel therapeutic targets, given their association with breast cancer through oncogenic signaling cascades and apoptosis regulation. Furthermore, upregulation of KIF12 and PPP1R1B suggest that acetate may potentially mediating therapeutic resistance in TNBC. These findings provide insights into microbial metabolic byproducts can impact TNBC progression and suggest that targeting acetate-driven metabolic and signaling pathways may offer innovative strategies for treatment of TNBC. Citation Format: Gabriel Borges-Velez, Diego N. Bracero-Sánchez, Liah M. Román-Calderón, Oscar A. Loperena-González, Ariana S. García-Lopez, Angel J. Amaral-Maisonet, Jeannette L. Salgado-Montilla, Esther A. Peterson-Peguero, Josue Perez-Santiago. Acetate-induced transcriptomic alterations reveal potential therapeutic targets in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6934.