MicroRNA-375 promotes tamoxifen resistance by stabilizing ERα via UBE3A-mediated ubiquitination

  • Int Immunopharmacol. 2026 Apr 15:175:116434. doi: 10.1016/j.intimp.2026.116434.
Dinglong Xue  1 ,  Yuyan Xie  2 ,  Jiayue Sun  2 ,  Jiazhuang Li  2 ,  Yaru Huang  2 ,  Yue Yang  2 ,  Longxu Liang  3 ,  Qi Li  4 ,  Guannan Mu  4 ,  Qingwei Meng  5 ,  Xuesong Chen  6 ,  Xiaoyi Huang  7
Affiliations
  • 1. Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin 150040, China. Electronic address: [email protected].
  • 2. Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin 150040, China.
  • 3. Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin 150040, China. Electronic address: [email protected].
  • 4. Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
  • 5. Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin 150040, China. Electronic address: [email protected].
  • 6. Department of Medical Oncology, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Harbin 150040, China. Electronic address: [email protected].
  • 7. Biotherapy Center, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: [email protected].
PMID: 41771217 DOI: 10.1016/j.intimp.2026.116434
Abstract

Background: Elucidating the molecular mechanisms of tumorigenesis and therapeutic resistance is essential for the development of effective treatments. Disruption of Estrogen Receptor alpha (ERα) signaling in ER+ Breast Cancer is a key driver of endocrine resistance, necessitating a deeper understanding of its regulatory mechanisms. MicroRNA-375 (miR-375) has been identified as a context-dependent regulator, functioning either as an oncogene or tumor suppressor in different Cancer types. This study aimed to explore the role of miR-375 in Breast Cancer progression and tamoxifen resistance.

Method: Quantitative Reverse transcription PCR (qRT-qPCR) was used to assess miR-375 expression in Breast Cancer tissues and cell lines. The correlation between miR-375 expression and overall survival in Breast Cancer patients was analyzed using the Kaplan-Meier plotter. Functional roles of miR-375 in Breast Cancer and tamoxifen sensitivity were evaluated via in vitro and in vivo gain- and loss-of-function assays. The molecular mechanism involving the miR-375-UBE3A-ERα signaling axis was investigated using dual-luciferase reporter assays, immunoprecipitation (IP), immunofluorescence (IF), and Ubiquitination analyses.

Results: miR-375 expression was significantly higher in ER+ Breast Cancer tissues compared to ER- samples. Patients with high miR-375 levels exhibited significantly worse overall survival. Overexpression of miR-375 enhanced ERα protein stability; consequently, this led to the acquisition of malignant phenotypes, including enhanced proliferation, migration, invasion, and tamoxifen resistance, along with reduced Apoptosis. These phenotypic effects were reversed upon miR-375 knockdown. Mechanistically, UBE3A, a direct target of miR-375, facilitated ERα degradation through the ubiquitin-proteasome pathway.

Conclusions: This study reveals that the miR-375-UBE3A-ERα axis contributes to Breast Cancer progression and tamoxifen resistance. Targeting miR-375 may represent a promising strategy to overcome endocrine resistance in ER+ Breast Cancer.

Keywords
ER(+) breast cancer; Tamoxifen sensitivity; Ubiquitination; miRNA.
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