Abstract 2575: DNA microarray and connectivity map analysis reveals estrogen-like activity of Chinese medicinal formula Si-Wu-Tang

Abstract

Abstract To pursue a systematic approach for discovery of potential mechanisms of action and new therapeutic use of traditional herbal medicines, we used DNA microarray, bioinformatics and the “Connectivity Map” (CMAP) analysis to investigate the gene expression profiling of Chinese herbal medicines. We demonstrated that this approach can be used to elucidate novel molecular mechanisms for the Chinese medicinal formula Si-Wu-Tang (SWT) which is widely used for women's health in Asian countries. The human breast cancer MCF-7 cells treated with beta-estradiol (E2, 0.1 µM) or SWT extract (0.0256, 0.256, and 2.56 mg/ml) for six hours showed significant gene expression changes. The differentially expressed genes related to SWT treatment were used to compare with the gene expression profiles of 1,309 compounds in the CMAP database. Such comparison revealed that the CMAP profile of E2-treated MCF-7 cells showed an excellent match with SWT treatment (permutation p<0.00001), consistent with SWT's widely claimed use for women's diseases and suggesting a phytoestrogen effect. Many genes strongly up-regulated by E2 were similarly upregulated by SWT, e.g., GREB1, a well-known estrogen regulated gene. Of interest with regard to the potential cancer preventive activity of SWT, the oncogenes MYBL1 and cyclin D1 were found to be strongly induced by E2 but not by SWT. In addition, SWT inhibited expression of estrogen receptor (ER)-alpha, but not ER-beta. Consistently, at low concentration (1.5 and 3.0 mg/ml), SWT stimulated MCF-7 (ER-positive) cell growth, while at high concentration (> 6.0 mg/ml), it inhibited the growth of MCF-7. The combination of SWT with tamoxifen, a selective estrogen receptor modulator, demonstrated enhanced growth inhibitory effects on MCF-7 cells. The results our study suggest that SWT may possess a non-toxic chemopreventive effect for human breast cancer. This study also demonstrated the feasibility of using microarray gene expression profiling in combination with the CMAP data mining to discover new molecular signature that are present in natural products. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2575. doi:1538-7445.AM2012-2575