Abstract 717: Title: Modulation of local cholesterol biosynthesis and response to oxidative stress in high-risk postmenopausal breast tissue with licochalcone A from licorice

Abstract

Abstract Background: The risk of breast cancer increases with age, despite a drastic decline in circulatory estrogen after menopause. Women at increased risk can reduce this by use of anti-endocrine agents, but often decline these drugs to their adverse effects. Therefore, alternative strategies with greater acceptability are needed. We have previously shown that licochalcone A (LicA) from licorice (Glycyrrhiza inflata) suppresses aromatase expression and activity, enhances the activity of detoxifying phase II metabolism enzymes, and reduces estrogen genotoxic metabolism in cell lines and animal models. However, its effects on the breast tissue of high-risk women have not been studied. We hypothesize that LicA creates a tumor preventive environment in the breast by locally modulating cholesterol and steroid hormone biosynthesis, and antioxidant/anti-inflammatory response. Methods: We prepared microstructures from fresh tissue of contralateral unaffected mastectomy specimens of 6 postmenopausal women with incident unilateral breast cancer. We exposed these microstructures to DMSO (control) and LicA (5 µM) for 24 h. After total RNA sequencing, we examined differential gene expression between treated and control samples using the limma R package. Enrichment results were generated by analyzing the up-regulated and down-regulated gene sets using Enrichr. A gene ontology (GO) pathway analysis was performed. The enriched pathways with combined enrichment scores > 4 and FDR < 0.05 were considered statistically significant. We performed confirmatory qPCR experiments in samples obtained from 18 additional women. Results: We observed significant (P < 0.05) upregulation up to 8-fold of antioxidant genes NQO1, HMOX1, G6PD, SQSTM1, PGD, and GPX2. Significant upregulation of Nrf2, the transcription factor involved in the activation of antioxidant enzymes, was evident. In addition, we observed the significant (P < 0.05) downregulation, ranging from 4 to 32-fold of cholesterol biosynthesis and transport genes, MSMO1, FDPS, EBP, SQLE, MVD, MVK, IDI1, DHCR7, NSDHL, FDFT1, LSS, ABCA1, ABCC3, ABCG1, steroid hormone biosynthesis genes HSD17B7, STS, CYP1A1, and CYP1B1, as well as lipid metabolism genes ACAT2, ACYL, FADS1, FADS2, ELOV6, CYP51A1, and LDLR. Some of the genes are shared between these pathways. The significant upregulation of the regulators of these pathways, SREBF1 and SREBF2 provided further confirmation. Conclusion: Our data suggest that LicA can lead to a tumor-preventive breast microenvironment by reducing cholesterol and steroid hormones and lowering oxidative stress mediators. These observations along with the popularity of natural products, suggests that LicA might be a good candidate to be studied further as an alternative breast cancer prevention agent. Citation Format: Atieh Hajirahimkhan, Elizabeth Bartom, Susan Clare, Seema A. Khan. Title: Modulation of local cholesterol biosynthesis and response to oxidative stress in high-risk postmenopausal breast tissue with licochalcone A from licorice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 717.