FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer

Estrogen receptor alpha (ER alpha) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. The molecular mechanisms underlying the up-regulation of ER alpha activity, however, remain poorly understood. We identified FK506-binding protein 52 (FKBP52) as a factor associated with poor prognosis of individuals with ERa-positive breast cancer. We found that FKBP52 interacts with breast cancer susceptibility gene 1 and stabilizes ER alpha, and is essential for breast cancer cell proliferation. FKBP52 depletion resulted in decreased ER alpha expression and proliferation in breast cancer cell lines, including MCF7-derived fulvestrant resistance (MFR) cells, suggesting that inhibiting FKBP52 may provide a therapeutic effect for endocrine therapy-resistant breast cancer. In contrast, FKBP51, a closely related molecule to FKBP52, reduced the stability of ER alpha. Consistent with these findings, FKBP51 was more abundantly expressed in normal tissues than in cancer cells, suggesting that these FKBPs may function in the opposite direction. Collectively, our study shows that FKBP52 and FKBP51 regulate ER alpha stability in a reciprocal manner and reveals a regulatory mechanism by which the expression of ER alpha is controlled.