FKBP52 and FKBP51 differentially regulate the stability of estrogen receptor in breast cancer
Menée in vitro et à l'aide d'une xénogreffe de cancer mammaire sur un modèle murin, cette étude met en évidence le rôle des immunophilines FKBP52 et FKBP51 dans la régulation de la stabilité du récepteur aux estrogènes ER alpha
Significance : Estrogen receptor
α (ERα) is a transcription factor that induces cell proliferation and exhibits increased expression in a large subset of breast cancers. We comprehensively searched for indicators of poor prognosis in ERα-positive breast cancer through the multiple databases, including interactome, transcriptome, and survival analysis, and identified FKBP52. We found that two immunophilins, FKBP52 and FKBP51, have opposing effects on ERα stability and propose that therapeutic targeting of FKBP52 could be useful for the prevention and treatment of ERα-positive breast cancers, including endocrine therapy
–resistant breast cancers.
Estrogen receptor
α (ERα) 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 ERα activity, however, remain poorly understood. We identified FK506-binding protein 52 (FKBP52) as a factor associated with poor prognosis of individuals with ERα-positive breast cancer. We found that FKBP52 interacts with breast cancer susceptibility gene 1 and stabilizes ERα, and is essential for breast cancer cell proliferation. FKBP52 depletion resulted in decreased ERα 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
α. 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 ERα stability in a reciprocal manner and reveals a regulatory mechanism by which the expression of ERα is controlled.
Proceedings of the National Academy of Sciences , résumé, 2022