Human estrogen receptor a (ER alpha) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ER alpha is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ER alpha regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ER alpha at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ER alpha. Hispolon treatment also inhibited expression of the ER alpha target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ER alpha in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. (C) 2015 Elsevier Inc. All rights reserved.