Abstract 3269A: 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer

Breast cancer (BC) remains one of the major causes of cancer deaths in women. 2Hydroxyflavanone (2HF), a constituent of citrus fruits, inhibits growth of human breast cancer cell lines in culture. The present study was undertaken to determine in vivo efficacy of 2HF against MDAMB231 human breast cancer xenografts. The 2HF administration retarded growth of MDAMB231 cells subcutaneously implanted in female nude mice without causing weight loss or any other side effects. The 2HF mediated suppression of MDAMB231 xenograft growth correlated with reduced cell proliferation as revealed by immunohistochemical analysis for Ki67 expression. Analysis of the vasculature in the tumors from 2HF treated mice indicated smaller vessel area compared with control tumors based on immunohistochemistry for angiogenesis marker CD31. The 2HF mediated inhibition of angiogenesis in vivo correlated with downregulation of vascular endothelial growth factor (VEGF) level in the tumor. Consistent with these results, 2HF treatment suppressed cell cycle regulators levels in cultured MDAMB231 cells. Moreover, the 2HF treated MDAMB231 cells exhibited reduced capacity for migration compared with vehicle-treated control cells. In addition, 2HF administration elicits apoptotic response as judged by annexin V and PI staining and TUNEL assay. 2HF treatment reduced the levels of ER alpha in ER positive MCF7 breast cancer cells. In conclusion, the present study demonstrates in vivo anticancer efficacy of 2HF against MDAMB231 xenografts in association with reduced cell proliferation and suppression of neovascularization. Our results indicate that 2HF is a promising anticancer agent for breast cancer due to its ability to collectively inhibit major regulators of breast cancer including RLIP76, ER alpha, and HER2. Interestingly, a spontaneously immortalized non-tumorigenic normal human mammary epithelial cell line (MCF10A) is significantly more resistant to 2HF mediated apoptosis compared with breast cancer cells, demonstrating selectivity of 2HF towards malignant breast cells. These preclinical observations merit clinical investigation to determine efficacy of 2HF against human breast cancers. (This work was supported in part by the Department of Defense grant W81XWH 16 1 0641. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Shireen Chikara, Lokesh Nagaprashantha, Jyotsana Singhal, David Horne, Sanjay Awasthi. 2-Hydroxyflavanone: A novel estrogen receptor alpha downregulator with potent antitumor effect in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3269A.