Abstract P1-11-01: Modulation of the high risk postmenopausal breast tissue genomic profiles with licorice and its bioactive compounds
Authors: Hajirahimkhan Atieh , Chen Shao-Nong , Pauli Guido F , Bartom Elizabeth , Clare Susan , Khan Seema A 
Published: March 2022

Abstract
Introduction: Breast cancer risk continues to rise following menopause, despite the cessation of ovarian estrogen synthesis. High risk women are often hesitant to take anti-endocrine therapies for breast cancer prevention. Therefore, alternative strategies with greater acceptability are needed. Popular botanicals for menopausal health such as licorice (Glycyrrhiza inflata, GI) and its bioactive compounds liquiritigenin (LigF, phytoestrogen) and licochalcone A (LicA, chalcone) have been studied for their targeted estrogenic and chemopreventive properties in vitro and in vivo. However, their effects on the breast tissue of high risk women are understudied. We hypothesize that these agents create a tumor preventive environment in the breast by locally modulating metabolism, steroid hormone biosynthesis, inflammation, antioxidant response, and proliferation. Methods: We prepared organoids from fresh surgically removed contralateral unaffected breast tissue of 6 high-risk postmenopausal women undergoing bilateral mastectomy due to incident unilateral breast cancer. We exposed these organoids to DMSO (control), GI (5 µg/mL), LigF (5 µM), and LicA (5 µM) for 24 h. After total RNA sequencing, we performed differential gene expression between treatments and controls 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 &gt; 4 and FDR &lt; 0.05 were considered statistically significant. Results: Among the top ranked biological pathways we observed significant upregulation of Nrf2 and phase II metabolism pathways, and the downregulation of steroid biosynthesis, metabolic processes such as estrogen metabolism, citrate cycle, serine and one carbon metabolism, as well as the cell cycle and DNA replication in GI treated samples. For LigF treated group, significant downregulation of inflammatory response, cell cycle, and the integrated breast cancer pathways were among the top ranked processes. For LicA treated samples, pathways associated with glutathione metabolism, Nrf2, response to oxidative stress, and unfolded protein response were significantly upregulated while steroid hormone biosynthesis, lipid metabolism, fatty acid biosynthesis, and glucose metabolism were among the top ranked downregulated pathways.Conclusions: Our data suggests that GI and its components LigF and LicA can modulate breast microenvironment by reducing inflammation, steroid hormone biosynthesis, cellular metabolism, and proliferation. They can also enhance protection against oxidative and cellular stress. These observations along with the popularity of natural products, suggests that licorice GI and its bioactive compounds might have the potential to create a tumor preventive breast microenvironment in high risk postmenopausal women, and need to be further studied.
Citation Format: Atieh Hajirahimkhan, Shao-Nong Chen, Guido F Pauli, Elizabeth Bartom, Susan Clare, Seema A Khan. Modulation of the high risk postmenopausal breast tissue genomic profiles with licorice and its bioactive compounds [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-11-01.