Regulation of Estrogen Signaling and Breast Cancer Proliferation by an Ubiquitin Ligase TRIM56

Abstract

Breast cancer ranks No.1 in women cancer worldwide, while 60-70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positive correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER alpha positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63 linked ubiquitination. In conclusion, our study reveals an interesting post-translational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER alpha positive breast cancer. Funding Statement: The project was supported by the National Science Foundation for Young Scientists of China (No. 8170110153, Ting Zhuang), the Joint Fund of the National Natural Science Foundation of China (No.U1604190, Jian Zhu; U1704169, Xiumin Li), the Program for Innovative Research Team (in Science and Technology) in University of Henan Province (No.15IRTSTHN025, Hui Wang), the National High Technology Research and Development Program of China (2012AA02A201-1), the Foundation of Henan Educational Committee (No.16A310014 and No.17A310025, Jian Zhu and Ting Zhuang), and the Program for Ph.D. starting research funding from Xinxiang Medical University (Ting Zhuang and Jian Zhu). This study is funded by graduate innovative practice base for clinical medicine of Xinxiang Medical University, Yashijie medical laboratory institute，School of laboratory medicine, Xinxiang Medical University Declaration of Interests: The authors claim no conflict of interest. Ethics Approval Statement: This study was reviewed and approved by the Ethical Board at Xinxiang Medical University. This usage of clinical samples was reviewed and approved by the Ethical Board at the Qilu Hospital of Shandong University with written informed consents from all the patients.