Estrogen-induced FXR1 promotes endocrine resistance and bone metastasis in breast cancer via BCL2 and GPX4
Estrogen signaling dysregulation plays a critical role in the development of anti-estrogen resistance and bone metastasis of ER+ mammary carcinoma. Using quantitative proteomic screening, we identified FXR1 as an estrogen-regulated RNA-binding protein associated with anti-estrogen resistance. Mechanistically, estrogen and IGF1 facilitate FXR1 protein translation via the PI3K/AKT/mTOR/EIF4E pathway. FXR1 enhances cellular resistance to apoptosis and ferroptosis by facilitating the maturation of BCL2 pre-mRNA and stabilizing GPX4 mRNA, respectively. Anti-estrogen resistant cells exhibit elevated FXR1 expression, and FXR1 depletion restores their sensitivity to tamoxifen. Moreover, combining FXR1 depletion with a ferroptosis inducer induces synergistic lethal in anti-estrogen resistant cells. Finally, we provide proof-of-concept evidence supporting FXR1 antagonism as a potential treatment for bone metastases in ER+ breast cancer. Our findings highlight FXR1 as a promising therapeutic target to improve existing therapeutic regimes for ER+ breast cancer patients.
Authors
- Yinzhong Shang (ORCID: https://orcid.org/0009-0003-9451-9005)
- Zhengsheng Wu (ORCID: https://orcid.org/0000-0002-6616-2745)
- Le Huang (ORCID: https://orcid.org/0000-0002-3940-6863)
- Peter E. Lobie (ORCID: https://orcid.org/0000-0002-8445-184X)
- Tao Zhu (ORCID: https://orcid.org/0000-0003-4130-1144)
- Xinghua Han (ORCID: https://orcid.org/0000-0002-0632-6955)
- Sheng Wu (ORCID: https://orcid.org/0000-0001-6630-3600)
- Mingming Wu (ORCID: https://orcid.org/0000-0001-8420-3750)
- Weijie Zhang (ORCID: https://orcid.org/0000-0003-2736-3445)
- Hao Wang (ORCID: https://orcid.org/0000-0001-6881-9977)
- Jiarui Wang (ORCID: https://orcid.org/0000-0002-0078-2191)
- Xin Ma (ORCID: https://orcid.org/0000-0001-8257-4670)
- Ting Cao (ORCID: https://orcid.org/0009-0007-9988-2160)
- Junchao Xu
- Vijay Pandey
Institutions
- University of Science and Technology of China (CN)
- Anhui Medical University (CN)
- Shenzhen Bay Laboratory (CN)
- Tsinghua–Berkeley Shenzhen Institute (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Frontiers in Cell and Developmental Biology
- Published
- 2025-03-24
- DOI
- https://doi.org/10.3389/fcell.2025.1563353
- Citations
- 3
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.42