التفاصيل البيبلوغرافية
| العنوان: |
Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer. |
| المؤلفون: |
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. |
| المصدر: |
Journal of Endocrinology; Mar2023, Vol. 256 Issue 3, p1-20, 20p |
| مصطلحات موضوعية: |
BREAST cancer, ESTROGEN, CELL cycle, ESTROGEN receptors, AROMATASE inhibitors, OVERALL survival |
| مستخلص: |
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 v alidation suggested miR-361-3p inhibitor effects might be mediated in part through F ANCA 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 vs paired 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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
