Breast cancer prevention with liquiritigenin

Breast cancer risk continues to increase post menopause. Anti-estrogen therapies are available to prevent postmenopausal breast cancer in high-risk women. However, their adverse effects have reduced acceptability and overall success in cancer prevention. Natural products such as hops (Humulus lupulus) and three pharmacopeial licorice (Glycyrrhiza) species have demonstrated estrogenic and chemopreventive properties, but little is known regarding their effects on aromatase expression and activity as well as pro-proliferation pathways in human breast tissue. We show that Gycyrrhiza inflata (GI) has the highest aromatase inhibition potency among these plant extracts. Moreover, phytoestrogens such as liquiritigenin which is common in all licorice species have potent aromatase inhibitory activity, which is further supported by computational docking of their structures in the binding pocket of aromatase. In addition, GI extract and liquiritigenin suppress aromatase expression in the breast tissue of high-risk postmenopausal women. Although liquiritigenin has estrogenic effects in vitro, with preferential activity through estrogen receptor (ER)-β, it reduces estradiol-induced uterine growth in vivo. It downregulates RNA translation, protein biosynthesis, and metabolism in high-risk women’s breast tissue. Finally, it reduces the rate of MCF-7 cell proliferation, with repeated dosing. Collectively, these data suggest that liquiritigenin has breast cancer prevention potential for high-risk postmenopausal women. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points. Comparative gene expression profiling analysis of RNA-seq data for breast tissue microstructures obtained from high-risk postmenopausal women and exposed to liquiritigenin for 24 h was performed.绝经后女性的乳腺癌发病风险仍持续升高。目前已有抗雌激素疗法可用于高风险绝经后女性的乳腺癌预防，但该类疗法的不良反应降低了其临床可接受性及癌症预防的整体效果。啤酒花（Humulus lupulus）及三种药典收录的甘草属（Glycyrrhiza）植物等天然产物已被证实具有雌激素样活性与化学预防特性，但目前对于它们在人体乳腺组织中对芳香化酶（aromatase）表达、活性以及促增殖通路的影响尚不清楚。本研究发现，在这些植物提取物中，Gycyrrhiza inflata（GI）的芳香化酶抑制活性最强。此外，所有甘草属植物中均含有的植物雌激素如甘草素（liquiritigenin）具有强效的芳香化酶抑制活性，这一点可通过其结构与芳香化酶结合口袋的计算机分子对接结果进一步验证。此外，GI提取物与甘草素可抑制高风险绝经后女性乳腺组织中的芳香化酶表达。尽管甘草素在体外实验中具有雌激素样活性，且优先通过雌激素受体β（estrogen receptor β, ER-β）发挥作用，但在体内可抑制雌二醇诱导的子宫增殖。它可下调高风险绝经后女性乳腺组织中的RNA翻译、蛋白质生物合成及代谢过程。最终，在反复给药后，它可降低MCF-7细胞的增殖速率。综上，上述实验数据表明，甘草素具备用于高风险绝经后女性乳腺癌预防的潜力。本研究随后针对4种不同细胞在两个时间点获取的RNA测序（RNA-seq）数据进行了基因表达谱分析。同时，针对从高风险绝经后女性体内获取并经甘草素处理24小时的乳腺组织微结构的RNA测序数据，开展了对比基因表达谱分析。