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

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-04, Vol.119 (15), p.e2110256119-e2110256119
Main Authors: Habara, Makoto, Sato, Yuki, Goshima, Takahiro, Sakurai, Masashi, Imai, Hiroyuki, Shimizu, Hideyuki, Katayama, Yuta, Hanaki, Shunsuke, Masaki, Takahiro, Morimoto, Masahiro, Nishikawa, Sayaka, Toyama, Tatsuya, Shimada, Midori
Format: Article
Language:English
Subjects:
Biological Sciences
Breast cancer
Breast Neoplasms - metabolism
Cell growth
Cell Line, Tumor
Cell proliferation
Depletion
Endocrine therapy
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogen receptors
Estrogens
Female
Fulvestrant
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Molecular modelling
Protein Stability
Receptors
Regulatory mechanisms (biology)
Stability
Tacrolimus
Tacrolimus Binding Proteins - metabolism
Tacrolimus-binding protein
Tumor cell lines
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 ERα. 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2110256119