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FKBP52 和 FKBP51 对乳腺癌中雌激素受体的稳定性具有不同的调节作用。

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

机构信息

Department of Veterinary Biochemistry, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, Yamaguchi, 753-8511, Japan.

Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.

出版信息

Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2110256119. doi: 10.1073/pnas.2110256119. Epub 2022 Apr 8.

DOI:10.1073/pnas.2110256119
PMID:35394865
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9169630/
Abstract

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.

摘要

雌激素受体 α（ERα）是一种转录因子，可诱导细胞增殖，并在大量乳腺癌中表达增加。然而，ERα 活性上调的分子机制仍知之甚少。我们发现 FK506 结合蛋白 52（FKBP52）是与 ERα 阳性乳腺癌患者预后不良相关的因素。我们发现 FKBP52 与乳腺癌易感基因 1 相互作用并稳定 ERα，并且是乳腺癌细胞增殖所必需的。FKBP52 的耗竭导致乳腺癌细胞系（包括 MCF7 衍生的氟维司群耐药（MFR）细胞）中 ERα 表达和增殖减少，表明抑制 FKBP52 可能为内分泌治疗耐药的乳腺癌提供治疗效果。相比之下，FKBP52 的密切相关分子 FKBP51 降低了 ERα 的稳定性。与这些发现一致的是，FKBP51 在正常组织中的表达量高于癌细胞，这表明这些 FKBP 可能以相反的方式发挥作用。总之，我们的研究表明 FKBP52 和 FKBP51 以相互的方式调节 ERα 的稳定性，并揭示了 ERα 表达受调控的一种调节机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/22180f312844/pnas.2110256119fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/21535dfbb855/pnas.2110256119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/fc27b7e7c486/pnas.2110256119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/d0b5f14624c2/pnas.2110256119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/387b7b791e62/pnas.2110256119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/83acf3176fc6/pnas.2110256119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/22bcae8a2feb/pnas.2110256119fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/55092b589f19/pnas.2110256119fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/22180f312844/pnas.2110256119fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/21535dfbb855/pnas.2110256119fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/fc27b7e7c486/pnas.2110256119fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/d0b5f14624c2/pnas.2110256119fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/387b7b791e62/pnas.2110256119fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/83acf3176fc6/pnas.2110256119fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/22bcae8a2feb/pnas.2110256119fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/55092b589f19/pnas.2110256119fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17e6/9169630/22180f312844/pnas.2110256119fig08.jpg

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[2]
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[6]
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[10]
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本文引用的文献

[1]
Calcineurin regulates the stability and activity of estrogen receptor α.

Proc Natl Acad Sci U S A. 2021-11-2

[2]
FKBP51 and FKBP52 regulate androgen receptor dimerization and proliferation in prostate cancer cells.

Mol Oncol. 2022-2

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Int J Mol Sci. 2021-3-5

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Sci Rep. 2019-9-4

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Genome Biol. 2019-5-13

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Adv Protein Chem Struct Biol. 2019-2-4

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Breast Cancer Res. 2019-2-28

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The Phosphorylated Estrogen Receptor α (ER) Cistrome Identifies a Subset of Active Enhancers Enriched for Direct ER-DNA Binding and the Transcription Factor GRHL2.

Mol Cell Biol. 2019-1-16

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