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siRNA therapeutics for breast cancer: recent efforts in targeting metastasis, drug resistance, and immune evasion

Published:August 19, 2019DOI:https://doi.org/10.1016/j.trsl.2019.08.005
      Small interfering RNA (siRNA) has an established and precise mode of action to achieve protein knockdown. With the ability to target any protein, it is very attractive as a potential therapeutic for a plethora of diseases driven by the (over)expression of certain proteins. Utilizing siRNA to understand and treat cancer, a disease largely driven by genetic aberration, is thus actively investigated. However, the main hurdle for the clinical translation of siRNA therapeutics is to achieve effective delivery of siRNA molecules to tumors and the site of action, the cytosol, within cancer cells. Several nanoparticle delivery platforms for siRNA have been developed. In this Review, we describe recent efforts in developing siRNA therapeutics for the treatment of cancer, with particular emphasis on breast cancer. Instead of conventionally targeting proliferation and apoptosis aspects of tumorigenesis, we focus on recent attempts in targeting cancer's metastasis, drug resistance, and immune evasion, which are considered more challenging and less manageable in clinics with current therapeutic molecules. siRNA can target all proteins, including traditionally undruggable proteins, and is thus poised to address these clinical challenges. Evidence also suggests that siRNA can be superior to antibodies or small molecule inhibitors when inhibiting the same druggable pathway. In addition to cancer cells, the role of the tumor microenvironment has been increasingly appreciated. Components in the tumor microenvironment, particularly immune cells, and thus siRNA-based immunotherapy, are under extensive investigation. Lastly, multiple siRNAs with or without additional drugs can be codelivered on the same nanoparticle to the same target site of action, maximizing their potential synergy while limiting off-target toxicity.

      Abbreviations:

      ATG (Autophagy Related), CCL (C-C chemokine ligand), CCR (C-C chemokine receptor), CD (Cluster of differentiation), CXCL (C-X-C chemokine ligand), CXCR (C-X-C chemokine receptor), CDK (Cyclin-dependent kinase), CK (Cytokeratin), DC (Dendritic cell), DOX (Doxorubicin), EPR (Enhanced permeability and retention), EGFR (Epidermal growth factor receptor), EMT (Epithelial-to-mesenchymal transition), ER (Estrogen receptor), ERK (Extracellular signal–regulated kinase), FDA (Food and drug administration), HER2 (Human epidermal growth factor receptor type 2), Lcn-2 (Lipocalin-2), IncRNA (Long non-coding RNA), MIF (Macrophage migration inhibitory factor), mTOR (Mammalian target of rapamycin), MMP (Matrix metalloproteinase), MSNP (Mesoporous silica nanoparticle), mRNA (Messenger RNA), MTDH (Metadherin), MEK (Mitogen-activated protein kinase kinase), nm (Nanometer), Pgp (P-glycoprotein), PITPNM (Phosphatidylinositol transfer protein membrane-associated), PIGF (Placental growth factor), PLK (Polo-like kinase), PLGA (Poly(lactic-co-glycolic acid)), PEG (NPolyethyleneglycol), PEI (polyethylenimine), PR (Progesterone receptor), PD-L1 (Programmed death-ligand 1), PTPN (Protein tyrosine phosphatase non-receptor), ROS (Reactive oxygen species), RNA (Ribonucleic acid), RISC (RNA-induced silencing complex), siRNA (Small-interfering RNA), TGF (Transforming growth factor), TNBC (Triple negative breast cancer), TAM (Tumor associated macrophage), TME (Tumor microenvironment), VEGF (Vascular endothelial growth factor)
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