Mechanisms of dihydrotestosterone action on resveratrol-induced anti-proliferation in breast cancer cells with different ERα status

// Yu-Tang Chin 1, * , Sheng-Huei Yang 2, * , Tung-Cheng Chang 3 , Chun A. Changou 2, 4, 5 , Hsuan-Yu Lai 1 , Earl Fu 6 , Wei-Chun HuangFu 1, 2 , Paul J. Davis 7, 8 , Hung-Yun Lin 1, 2 , Leroy F. Liu 1 1 Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan 2 PhD program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 3 Division of Colorectal Surgery Department of Surgery, Taipei Medical University-Shuang-Ho Hospital, New Taipei City, Taiwan 4 Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan 5 Core Facility, Taipei Medical University, Taipei, Taiwan 6 Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan 7 Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA 8 Albany Medical College, Albany, New York, USA * These authors have contributed equally to this work Correspondence to: Wei-Chun HuangFu, e-mail: clarehf@tmu.edu.tw Hung-Yun Lin, e-mail: linhy@tmu.edu.tw Keywords: resveratrol, DHT, estrogen receptor-α, integrin αvβ3, breast cancer Received: May 28, 2015 Accepted: September 25, 2015 Published: October 06, 2015 ABSTRACT Dihydrotestosterone (DHT) has been shown to promote breast cancer growth via different mechanisms. In addition to binding to ERα, the DHT membrane receptor exists on integrin αvβ3. Resveratrol induces p53-dependent apoptosis via plasma membrane integrin αvβ3. Resveratrol and DHT signals are both transduced by activated ERK1/2; however, DHT promotes cell proliferation in cancer cells, whereas resveratrol is pro-apoptotic. In this study, we examined the mechanism by which DHT inhibits resveratrol-induced apoptosis in human ERα positive (MCF-7) and negative (MDA-MB-231) breast cancer cells. DHT inhibited resveratrol-stimulated phosphorylation of Ser-15 of p53 in a concentration-dependent manner. These effects of DHT on resveratrol action were blocked by an ERα antagonist, ICI 182,780, in MCF-7 breast cancer cells. DHT inhibited resveratrol-induced nuclear complex of p53-COX-2 formation which is required p53-dependent apoptosis. ChIP studies of COX-2/p53 binding to DNA and expression of p53-responsive genes indicated that DHT inhibited resveratrol-induced p53-directed transcriptional activity. In addition, DHT did inhibit resveratrol-induced COX-2/p53-dependent gene expression. These results suggest that DHT inhibits p53-dependent apoptosis in breast cancer cells by interfering with nuclear COX-2 accumulation which is essential for stimulation of apoptotic pathways. Thus, the surface receptor sites for resveratrol and DHT are discrete and activate ERK1/2-dependent downstream effects on apoptosis that are distinctive. These studies provide new insights into the antagonizing effects of resveratrol versus DHT, an important step toward better understanding and eventually treating breast cancer. It also indicates the complex pathways by which apoptosis is induced by resveratrol in DHT-depleted and -repleted environments.