2. Academic Validation
  3. Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer

Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer

  • EMBO Mol Med. 2023 Jul 17;e17248. doi: 10.15252/emmm.202217248.
Coralie Poulard # 1 2 3,  Thuy Ha Pham # 1 2 3,  Youenn Drouet 4,  Julien Jacquemetton 1 2 3,  Ausra Surmielova 1 2 3,  Loay Kassem 5,  Benoite Mery 1 2 3 6,  Christine Lasset 4 7,  Jonathan Reboulet 8,  Isabelle Treilleux 1 2 3 9,  Elisabetta Marangoni 10,  Olivier Trédan # 1 2 3 6,  Muriel Le Romancer # 1 2 3
Affiliations

Affiliations

  • 1 Université de Lyon, Lyon, France.
  • 2 Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  • 3 CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
  • 4 Département Prévention et Santé Publique, Centre Léon Bérard, Lyon, France.
  • 5 Clinical Oncology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
  • 6 Oncology Department, Centre Leon Bérard, Lyon, France.
  • 7 CNRS UMR 5558 LBBE, Université de Lyon, Villeurbanne, France.
  • 8 Lipics Services, Lyon, France.
  • 9 Pathology Department, Centre Leon Bérard, Lyon, France.
  • 10 Translational Research Department, Institut Curie, Paris, France.
  • # Contributed equally.
PMID: 37458145 DOI: 10.15252/emmm.202217248
Abstract

Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of Estrogen Receptor alpha (ERα)-positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti-estrogens to guide treatment decision. Here, using two independent cohorts of breast Cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen-sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα-positive breast tumors that could be used to enhance the response of breast Cancer patients to endocrine therapy, by fostering its nuclear expression.

Keywords

PRMT5; arginine methylation; estrogen receptor; resistance; tamoxifen.

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