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Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer.
Zamarbide Losada, J N; Sulpice, E; Combe, S; Almeida, G S; Leach, D A; Choo, J; Protopapa, L; Hamilton, M P; McGuire, S; Gidrol, X; Bevan, C L; Fletcher, C E.
Afiliação
  • Zamarbide Losada JN; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Sulpice E; Université Grenoble Alpes, CEA, INSERM, BIG, BGE, Grenoble, France.
  • Combe S; Université Grenoble Alpes, CEA, INSERM, BIG, BGE, Grenoble, France.
  • Almeida GS; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Leach DA; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Choo J; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Protopapa L; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Hamilton MP; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
  • McGuire S; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
  • Gidrol X; Université Grenoble Alpes, CEA, INSERM, BIG, BGE, Grenoble, France.
  • Bevan CL; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
  • Fletcher CE; Imperial Centre for Translational and Experimental Medicine, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK.
J Endocrinol ; 256(3)2023 03 01.
Article em En | MEDLINE | ID: mdl-36622663
Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias da Mama / MicroRNAs Limite: Female / Humans Idioma: En Revista: J Endocrinol Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias da Mama / MicroRNAs Limite: Female / Humans Idioma: En Revista: J Endocrinol Ano de publicação: 2023 Tipo de documento: Article