期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2110256119
关键词
BRCA1; breast cancer; estrogen receptor; FKBP; protein stability
资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan Fusion Oriented Research for Disruptive Science and Technology [18H02681, 20K21503]
- MSD Life Science Foundation
- Shinnihon Foundation of Advanced Medical Treatment Research
- Grants-in-Aid for Scientific Research [20K21503, 18H02681] Funding Source: KAKEN
FKBP52 is associated with poor prognosis of ERα-positive breast cancer, stabilizes ERα, and promotes breast cancer cell proliferation, while FKBP51 reduces the stability of ERα. FKBP51 is more abundantly expressed in normal tissues than in cancer cells.
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.
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