Alteration of the ERα/ERβ balance is a critical step in breast cancer development and progression, and selective restoration of the activity of estrogen receptors has been proposed as one of the major therapeutic approaches for breast cancer. In this issue of JCI, Cheng et al. show that, by differentially modulating the stability of ERα and ERβ, PES1 increases the ERα/ERβ ratio and triggers breast tumor growth. These findings highlight PES1 as a potential target for the treatment of breast cancer.
Christoforos Thomas, Jan-Åke Gustafsson
A model of PES1 activity in breast cancer.
PES1 promotes mammary tumor growth and plays a role in sensitivity to endocrine therapy by regulating the stability of ERs. PES1 reduces the interaction of ERα with the E3 ubiquitin ligase CHIP, thereby blocking ubiquitylation and degradation of ERα. In contrast, by inducing the interaction of CHIP with ERβ, PES1 targets ERβ for degradation. This leads to an increase in the ERα/ERβ protein ratio that has been shown to influence breast tumor growth. Since ERα levels determine tamoxifen sensitivity in breast cancer, PES1 may have a role in predicting response to endocrine therapy. These findings also suggest that PES1 may represent a novel therapeutic target in breast cancer and may serve as a useful biomarker for endocrine therapy resistance. Ub, ubiquitin.