UCH-L1-mediated down-regulation of estrogen receptor α contributes to insensitivity to endocrine therapy for breast cancer

Xi Sha Chen, Kuan Song Wang, Wei Guo, Lan Ya Li, Pian Yu, Xin Yuan Sun, Hai Yan Wang, Yi Di Guan, Yong Guang Tao, Bo Ni Ding, Ming Zhu Yin, Xing Cong Ren, Yi Zhang, Ce Shi Chen, Yuan Chao Ye, Jin Ming Yang, Yan Cheng

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.

Original languageEnglish
Pages (from-to)1833-1848
Number of pages16
JournalTheranostics
Volume10
Issue number4
DOIs
StatePublished - 2020

Bibliographical note

Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (No 81422051, 31401208 and 81472593 to YC), and the Hunan Natural Science Foundation of China No 2016JJ1020 and 2015JJ2150.

Publisher Copyright:
© The author(s).

Keywords

  • EGFR
  • ER-negative breast cancer
  • Endocrine therapy
  • Estrogen receptor α
  • Ubiquitin carboxyl terminal hydrolase-L1

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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