Reprogramming SREBP1-dependent lipogenesis and inflammation in high-risk breast with licochalcone A: a novel path to cancer prevention

Background Anti-estrogens have had limited impact on breast cancer (BC) prevention. Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER-agnostic BC prevention. Methods We evaluated antiproliferative effects of LicA in seven breast cell lines and its suppression of ER+ and ER− xenograft tumors in mice. High-risk human breast tissue was treated with LicA ex vivo , followed by RNA sequencing and metabolism flux modeling. Confirmatory testing was performed in an independent specimen set and ER+/− BC cell lines using NanoString metabolic panel, proteomics, western blots, and spatiotemporally resolved cholesterol quantification in single cells. Results LicA suppressed proliferation in vitro and xenograft tumor growth in vivo . It downregulated pivotal steps in PI3K-AKT-SREBP1-dependent lipogenesis, suppressed PI3K and AKT phosphorylation, SREBP1 protein expression, and cholesterol levels in the plasma membrane inner leaflet, to the levels in normal breast cells. LicA also suppressed prostaglandin E2 synthesis and PRPS1-catalyzed de novo nucleotide biosynthesis, stalling proliferation; further evident by reduced MKI67 and BCL2 proteins. Conclusions LicA targets SREBP1, a central regulator of lipogenesis and immune response, reducing pro-tumorigenic aberrations in lipid homeostasis and inflammation. It is a promising non-endocrine candidate for BC prevention.