Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guérin efficacy in bladder cancer

// Zhiqun Shang 1,2 ,Yanjun Li 1 , Iawen Hsu 2 , Minghao Zhang 1 , Jing Tian 1,2 , Simeng Wen 1,2,* , Ruifa Han 1 , Edward M. Messing 2,* , Chawnshang Chang 1,2 , Yuanjie Niu 1,2 and Shuyuan Yeh 1,2 1 Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, The 2nd Hospital of Tianjin Medical University, Tianjin, China 2 George Whipple Lab for Cancer Research, Departments of Urology, Pathology and the Cancer Center, University of Rochester, Rochester, New York, United States of America * co-authors Correspondence to: Yuanjie Niu, email: // Shuyuan Yeh, email: // Keywords : Bacillus Calmette-Guerin, bladder cancer, estrogen, estrogen receptor alpha Received : October 11, 2015 Accepted : January 24, 2016 Published : April 15, 2016 Abstract Recent studies showed the potential linkage of estrogen/estrogen receptor signaling with bladder tumorigenesis, yet detailed mechanisms remain elusive. Here we found a new potential therapy with the combination of Bacillus Calmette Guerin (BCG) and the anti-estrogen ICI 182,780 led to better suppression of bladder cancer (BCa) than BCG alone. Mechanism dissection found ICI 182,780 could promote BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release, which may enhance BCG-induced suppression of BCa cell growth via recruiting more monocytes/macrophages to BCa cells and increased TNF-α release. Consistently, in vivo studies found ICI 182,780 could potentiate the anti-BCa effects of BCG in the carcinogen-induced mouse BCa models. Together, these in vitro and in vivo results suggest that combining BCG with anti-estrogen may become a new therapeutic approach with better efficacy to suppress BCa progression and recurrence.