Reciprocal Regulation Of Er Alpha And Er Beta Stability And Activity By Diptoindonesin G

ER beta is regarded as a "tumor suppressor" in breast cancer due to its anti-proliferative effects. However, unlike ER alpha, ER beta has not been developed as a therapeutic target in breast cancer due to loss of ER beta in aggressive cancers. In a small-molecule library screen for ER beta stabilizers, we identified Diptoindonesin G (Dip G), which significantly increases ER beta protein stability while decreasing ER alpha protein levels. Dip G enhances the transcription and anti-proliferative activities of ER beta, while attenuating the transcription and proliferative effects of ER alpha. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ER alpha and ER beta. Thus, Dip G is a dual-functional moiety that reciprocally controls ER alpha and ER beta protein stability and activities via an indirect mechanism. The ER beta stabilization effects of Dip G may enable the development of ER beta-targeted therapies for human breast cancers.