Abstract 7306: Licochalcone A is an excellent candidate for preventing luminal and non-luminal breast cancers

Abstract

Abstract Breast cancer (BC) risk reducing drugs have minimal impact due to their adverse effects and low acceptance by risk-eligible women. Further, they are ineffective against hormone receptor negative (HR-) BC. Novel agents with reduced toxicity and sufficient efficacy that extends beyond HR+ BC are needed. We showed previously that licochalcone A (LicA) from licorice has antioxidant/anti-inflammatory effects, inhibits aromatase, and blocks estrogen genotoxic metabolism. We hypothesize that LicA prevents HR+ and HR- BC through reprogramming metabolism and antioxidant pathways. We prepared microstructures from the fresh tissue of contralateral unaffected breast of 6 postmenopausal women with unilateral BC. After exposing them to DMSO (control) or LicA (5 µM), we performed total RNA sequencing followed by differential gene expression, pathway identification, and metabolism flux analyses. The NanoString metabolism panel was employed in 6 additional subjects. We performed live cell imaging to monitor proliferation of HR- and HR+ pre-malignant and malignant, as well as BRCA mutated cells. Xenograft models of HR+ and HR- tumors were established in female nude mice followed by 28-day treatment with vehicle or LicA (80 mg/kg.day, s.c.) and monitoring the tumor growth. Using LC-MS/MS we measured LicA in the blood and various tissues of intact BALB/c female mice receiving oral LicA (100 mg/kg) and assessed PK using Phoenix Platform. We observed significant (combined enrichment scores > 4 and FDR < 0.05) upregulation of antioxidant genes (up to 8-fold), consistent with upregulation of NRF2 and the thioredoxin system. This was accompanied by significant downregulation of RELA- and NF-kB1-dependent inflammatory pathways. In addition, we observed decreased expression of PI3K-AKT genes and the pro-adipogenic transcription factors SREBF1 and SREBF2, which may explain the downregulation (4 to 32-fold) of cholesterol biosynthesis, transport, and lipid metabolism genes. Metabolism studies confirmed these data and demonstrated a robust increase in the pentose phosphate shunt and NAD(P)H generation without enhancing ribose 5 phosphate formation, suggesting an antioxidant and antiproliferative environment. LicA also suppressed proliferation of pre-malignant and malignant cells, with sustained effects on aggressive cell lines at doses <10 µM. It reduced tumor growth in luminal (P = 0.008) and triple negative (P = 0.001) xenograft models. Oral bioavailability in serum and breast was in the low micromolar range and was sufficient to show efficacy.Our data suggest that LicA is an excellent candidate for both HR+ and HR- BC prevention by reprogramming metabolism and antioxidant pathways leading to decreased proliferation. Our next study will test an optimized oral formulation of LicA in intraductal models of HR+ and HR- precancer lesions in immunocompetent mice to further establish its preventive efficacy. Citation Format: Atieh Hajirahimkhan, Elizabeth T. Bartom, Sriram Chandrasekaran, Ruohui Chen, Jeremy J. Johnson, Susan E. Clare, Seema A. Khan. Licochalcone A is an excellent candidate for preventing luminal and non-luminal breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7306.