Estrogen-induced FXR1 Promotes Endocrine Resistance and Bone metastasis in Breast Cancer via BCL2 and GPX4

Yinzhong Shang ¹ Tingfang Cao ¹ Xin Ma ² Le Huang ¹ Mingming Wu ¹ Junchao Xu ¹ Jiarui Wang ¹ Hao Wang ³ Sheng Wu ¹ Vijay Pandey ² Zhengsheng Wu ³ Weijie Zhang ¹ Peter E Lobie ² Xinghua Han ^1* Tao Zhu ^1,4*

• ¹ Division of Life Sciences and Medicine, The First Affiliated Hospital of University of Science and Technology of China Anhui Provincial Hospital, Hefei, Anhui Province, China
• ² Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
• ³ Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
• ⁴ University of Science and Technology of China, Hefei, China

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.