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

ABSTRACT: This study investigates the effects of Licochalcone A (LicA) on protein stability in breast cancer cells using Proteome Integral Solubility Alterations (PISA) proteomics. We treated MCF-7 (ER+) and MDA-MB-231 (ER-) cells with LicA (10 µM) for 24 hours and subjected them to temperature-dependent protein solubility profiling. Thermal denaturation assays (40-65°C) followed by LC-MS/MS analysis with TMT labeling were performed to identify differentially stabilized and destabilized proteins. Our results indicate that LicA significantly destabilizes proteins involved in SREBP1-dependent lipogenesis, PI3K-AKT signaling, and NF-kB-mediated inflammation, while stabilizing pathways associated with antioxidant defense and metabolic reprogramming. These findings suggest a mechanism by which LicA alters the breast cancer proteome, leading to reduced tumor proliferation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Shao Huan Samuel Weng

LAB HEAD: Atieh Hajirahimkhan

PROVIDER: PXD061086 | Pride | 2025-09-29

REPOSITORIES: Pride

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			Action	DRS
	EC_08292024_MCF-7_MatchedProteins_heatmap_data.xlsx	Xlsx
	EC_08292024_MCF-7_TMT6plex_Fr1.raw	Raw
	EC_08292024_MCF-7_TMT6plex_Fr2.raw	Raw
	EC_08292024_MCF-7_TMT6plex_Fr3.raw	Raw
	EC_08292024_MCF-7_TMT6plex_Fr4.raw	Raw

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

Project description:Anti-estrogens have had a 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. We demonstrated that LicA significantly reduced proliferation in seven human breast cell lines and suppressed ER+ and ER- xenograft tumors in mice. We confirmed these observations ex vivo in contralateral unaffected breast (CUB) of women with unilateral sporadic BC, and breast cancer cell lines using RNA sequencing, metabolism flux modeling, confirmatory NanoString metabolic pathway panel analysis in independent sets of specimens, proteomics, and western blots. We found that LicA targets sterol regulatory element binding protein 1 (SREBP1) with subsequent metabolic-inflammatory changes, lowering spatiotemporally resolved cholesterol levels inside malignant cells to the levels in normal mammary cells. Mechanistically, in CUBs we observed that LicA downregulated PI3K-AKT-SREBP1-dependent lipogenesis, NF-kB-dependent inflammation, and de novo nucleotide biosynthesis, stalling proliferation. Studies in cell lines showed suppression of PI3K and AKT phosphorylation, SREBP1 protein expression, and the SREBP1-dependent enzymes such as ACAT2, ACLY, FASN, SCD, consistent with reduced NEDD8 required for SREBP1 stabilization. We found significant reduction in NF-kB expression, its nuclear translocation mediator karyopherin β1, and prostaglandin E2 synthesis. We demonstrated a reduction in PRPS1-catalyzed de novo nucleotide biosynthesis, and downregulation of proliferative markers MKI67, RRM2, and the survival marker BCL2. LicA reduces pro-tumorigenic aberrations in lipid homeostasis and inflammation through SREBP1. It is a promising non-endocrine candidate for BC prevention. Future studies in immunocompetent BC prevention models are warranted.

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