2. Academic Validation
  3. G protein-coupled estrogen receptor reduces the breast cancer cell survival by regulating the IRE1α/miR-17-5p/TXNIP pathway

G protein-coupled estrogen receptor reduces the breast cancer cell survival by regulating the IRE1α/miR-17-5p/TXNIP pathway

  • J Steroid Biochem Mol Biol. 2025 Sep:252:106770. doi: 10.1016/j.jsbmb.2025.106770.
Maryam Mohammad-Sadeghipour 1,  Mohammad Hadi Nematollahi 2,  Maryam Sahebazzamani 3,  Hassan Ahmadinia 4,  Mohammad Reza Hajizadeh 5,  Mehdi Mahmoodi 6,  Amirhossein Sahebkar 7
Affiliations

Affiliations

  • 1 Molecular Medicine Research Center, Inistitute of Basic Medical Sciences Research, Rafsanjan University of Medical Sciences, Rafsanjan City, Rafsanjan Province, Iran; Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman City, Kerman Province, Iran.
  • 2 Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman City, Kerman Province, Iran.
  • 3 Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman City, Kerman Province, Iran.
  • 4 Department of Biostatistics, Rafsanjan University of Medical Sciences, Rafsanjan City, Rafsanjan Province, Iran.
  • 5 Molecular Medicine Research Center, Inistitute of Basic Medical Sciences Research, Rafsanjan University of Medical Sciences, Rafsanjan City, Rafsanjan Province, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan City, Rafsanjan Province, Iran.
  • 6 Molecular Medicine Research Center, Inistitute of Basic Medical Sciences Research, Rafsanjan University of Medical Sciences, Rafsanjan City, Rafsanjan Province, Iran; Department of Clinical Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman City, Kerman Province, Iran. Electronic address: me.mahmoodi@kmu.ac.ir.
  • 7 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: amir_saheb2000@yahoo.com.
PMID: 40328365 DOI: 10.1016/j.jsbmb.2025.106770
Abstract

This study aimed to explore whether GPER can induce the UPR response in the SKBR3 cell line through ER and IREα activation, and to assess whether this response leads to cell survival or cell death. Additionally, the study sought to evaluate the impact of this response on cell behaviors such as Apoptosis, migration, and drug resistance. To activate the UPR and induce ER stress, we treated the MCF10A cell line with 0.5 µg/ml TUN for 24 and 48 h. The expression levels of XBP-1 and C/EBP homology protein (CHOP) genes (ER stress markers) were measured using the qRT-PCR technique. The MCF10A + TUN cell line was used as a positive control. To determine the optimal doses of G1 and tamoxifen (TAM), we evaluated GPER expression using qRT-PCR analysis. Cells were then treated with various doses of G1 (1000 nM), G15 (1000 nM), and TAM (2000 nM), both individually and in combination (G1 + G15, TAM + G15, G1 + TAM), for 24 and 48 h. We measured the expression of GPER, IRE1α, MiR-17-5p, TXNIP, ABCB1, and ABCC1 genes. Apoptosis was assessed via flow cytometry, and cell migration was examined using the wound-healing assay. Our results demonstrated that GPER activation by G1 and TAM significantly increased IRE1α expression in SKBR3 cells. This activation, through its RIDD activity, cleaved miR-17-5p and initiated the UPR death response. The upregulation of the TXNIP gene expression enhanced Apoptosis and chemotherapy sensitivity while decreasing cell migration. Interestingly, these effects were notably reversed by G15 treatment. In summary, the GPER/IRE1α/miR-17-5p/TXNIP axis plays a key role in the UPR pro-death response, promoting programmed cell death, reducing migration, and decreasing drug resistance in SKBR3 cells.

Keywords

Breast cancer; Drug resistance; G protein-coupled estrogen receptor; Inositol-Requiring Enzyme 1; MiR-17-5p; Thioredoxin interacting protein; Unfolded protein response.

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