Abstract 6339: Reprogramming SREBP1-dependent metabolism and inflammation in high-risk breast with licochalcone A for the prevention of breast cancer

Abstract Breast cancer (BC) risk-reducing drugs have minimal impact due to their adverse effects and low acceptance. Novel non-endocrine agents with reduced toxicity and efficacy beyond HR+ BC are needed. We recently showed that in high-risk women’s breast treated with licochalcone A (LicA) ex vivo, changes in metabolism flux led to reduced proliferation, NF-kB-dependent inflammation, and SREBP1-dependent lipogenesis. Additionally, LicA suppressed the proliferation of pre-malignant and malignant breast cell lines (HR+ and HR-) and their xenografts in mice. Now we present confirmatory evidence that LicA prevents BC by reducing SREBP1-dependent metabolism and inflammation. We also show the promising pharmacokinetic (PK) profiles of our novel oral formulations. We performed NanoString metabolism panel assay in MDA-MB-231 (HR-) and MCF-7 (HR+) cells treated with LicA (10 µM, 24 h) and analyzed data by ROSALIND. We also conducted Proteome Integral Solubility Alteration (PISA) proteomics and Enrichr analysis to confirm transcriptomic data and the main targets of LicA. We validated the findings with western blots. In addition, we evaluated spatiotemporal changes in cholesterol concentrations in the inner leaflet of the plasma membrane. Five proprietary novel formulations of LicA were developed and administered orally and intravenously to female BALB/c mice and Sprague-Dawley rats followed by LC-MS/MS analysis of the plasma and mammary tissue, and PK modeling using SAAM II. We observed significant (adj P < 0.05) upregulation of anti-inflammatory signals (up to 9-fold) such as HMOX1, and downregulation (up to 6-fold) of NF-kB-dependent inflammatory pathways such as prostaglandin E2 synthesis at the level of genes and proteins. We also observed significant downregulation of SREBP1-dependent lipogenesis signals such as ACAT2, FASN, SCD, and proliferation markers such as MKI67. Proteomics results further revealed a reduction in neddylation responsible for stabilizing SREBP1, and a metabolic shift from lipogenesis to the degradation of fatty acids and branched amino acids, and an enhanced TCA cycle. Western blots revealed significant suppression of SREBP1 (4-fold), and the reduced phosphorylation of PI3K (5-fold) and AKT (6-fold, at Ser 473). These results were confirmed by cholesterol depletion in the inner leaflet of the plasma membrane in HR- (8-fold) and HR+ (4-fold) cells. These results demonstrate that LicA reduces cell proliferation by suppressing SREBP1-dependent lipogenesis and inflammation. Our novel oral formulation of LicA, L13 showed promising PK (Cmax ≈ 6 µM, T1/2 = 26 h) suitable for BC prevention efficacy. Our data suggests that reprogramming SREBP1-dependent metabolism and inflammation by LicA prevents BC regardless of HR status. We will test L13 in immunocompetent models of BC to further establish its preventive efficacy. Citation Format: Atieh Hajirahimkhan, Elizabeth T. Bartom, xingyu Guo, Kyli Berkley, Ruohui Chen, Wonhwa Cho, Michael Avram, Susan E. Clare, Seema A. Khan. Reprogramming SREBP1-dependent metabolism and inflammation in high-risk breast with licochalcone A for the prevention of 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 6339.