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@article{Fletcher:2023:10.1530/JOE-22-0229,
author = {Fletcher, C and Zamarbide, Losada J and Sulpice, E and Combe, S and Serrano, de Almeida G and Leach, D and Choo, J and Protopapa, P and Hamilton, M and McGuire, S and Gidrol, X and Bevan, C},
doi = {10.1530/JOE-22-0229},
journal = {Journal of Endocrinology},
pages = {1--20},
title = {Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer},
url = {http://dx.doi.org/10.1530/JOE-22-0229},
volume = {256},
year = {2023}
}

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TY  - JOUR
AB  - 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.
AU  - Fletcher,C
AU  - Zamarbide,Losada J
AU  - Sulpice,E
AU  - Combe,S
AU  - Serrano,de Almeida G
AU  - Leach,D
AU  - Choo,J
AU  - Protopapa,P
AU  - Hamilton,M
AU  - McGuire,S
AU  - Gidrol,X
AU  - Bevan,C
DO  - 10.1530/JOE-22-0229
EP  - 20
PY  - 2023///
SN  - 0022-0795
SP  - 1
TI  - Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-responsive and endocrine-resistant breast cancer
T2  - Journal of Endocrinology
UR  - http://dx.doi.org/10.1530/JOE-22-0229
UR  - https://joe.bioscientifica.com/view/journals/joe/256/3/JOE-22-0229.xml
UR  - http://hdl.handle.net/10044/1/102735
VL  - 256
ER  -

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