Apoptosis-modulatory miR-361-3p as a novel treatment target in endocrine-resistant breast cancer.
Joanna Zamarbide LosadaEric SulpiceStephanie CombeGilberto Serrano de AlmeidaDamien A LeachJosephine Ann Mun Yee ChooPantelitsa ProtopapaMark P HamiltonSean Eric McGuireXavier GidrolCharlotte L BevanClaire Emily FletcherPublished in: The Journal of endocrinology (2023)
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 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 potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as 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 versus 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 potential new treatment for drug-responsive and -resistant advanced BC.
Keyphrases
- cell cycle arrest
- cell death
- pi k akt
- estrogen receptor
- signaling pathway
- drug resistant
- rna seq
- high throughput
- oxidative stress
- endoplasmic reticulum stress
- induced apoptosis
- cell proliferation
- single cell
- cancer therapy
- case report
- poor prognosis
- pregnant women
- high resolution
- artificial intelligence
- newly diagnosed
- single molecule
- risk assessment
- drug delivery
- cystic fibrosis
- machine learning
- ejection fraction
- long non coding rna
- prognostic factors
- multidrug resistant
- adipose tissue
- climate change
- squamous cell
- lymph node
- mass spectrometry
- acinetobacter baumannii
- breast cancer risk
- human health
- binding protein
- polycystic ovary syndrome
- case control