ERβ is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small-molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ERβ protein stability while decreasing ERα protein levels. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual-functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.
Bibliographical noteFunding Information:
We thank Dr. Kenneth Satyshur for the molecular docking of CHIP E3 ligase and Dip G, and Dr. Weibo Luo and Gregg L. Semenza for providing the CHIP ΔU-Box and ΔTPR plasmids. We acknowledge Dr. Richard R. Burgess for critical review of the manuscript. T.J. was supported by T32ES007015 and PHRMA 2012080067. This project is supported by DOD ERA of HOPE Scholar Award ( W81XWYH-11-1-0237 ) to W.X. and also by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS) grant UL1TR000427 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
© 2015 Elsevier Ltd. All rights reserved.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry