Journal article
Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer
Proceedings of the National Academy of Sciences - PNAS, Vol.121(13), pp.e2306814121-e2306814121
03/26/2024
DOI: 10.1073/pnas.2306814121
PMCID: PMC10990146
PMID: 38513102
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody–drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor β (ERβ) in TNBC, but the detailed molecular mechanisms downstream ERβ activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERβ agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp 439 and Lys 443 of ERβ were critical for the binding between U2AF1 and ERβ. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase ( OPLAH ) could affect its enzymatic activity and is essential for ERβ-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERβ activation in TNBC, which provides rationale for ERβ activation–based single or combined therapy for patients with TNBC.
Details
- Title: Subtitle
- Activation of ERβ hijacks the splicing machinery to trigger R-loop formation in triple-negative breast cancer
- Creators
- Dongfang Wang - Sichuan UniversityMuya Tang - Sichuan UniversityPeidong Zhang - Sichuan UniversityKailin Yang - Cleveland ClinicLiang Huang - Sichuan UniversityMengrui Wu - Sichuan UniversityQiuhong Shen - Sichuan UniversityJing Yue - Sichuan UniversityWei Wang - Huzhou Women and Children's HospitalYanqiu Gong - Sichuan UniversityMargaret Warner - University of HoustonLunzhi Dai - Sichuan UniversityHaihuai He - Sichuan UniversityZhengnan Yang - Sichuan UniversityJan-Ake Gustafsson - University of HoustonShengtao Zhou - Sichuan University
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.121(13), pp.e2306814121-e2306814121
- DOI
- 10.1073/pnas.2306814121
- PMID
- 38513102
- PMCID
- PMC10990146
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Language
- English
- Date published
- 03/26/2024
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696561902771
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