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

Published:August 19, 2019DOI:
      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.


      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)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2019.
        CA Cancer J Clin. 2019; 69: 7-34
        • Weinstein I.B.
        • Joe A.
        Oncogene Addiction.
        Cancer Res. 2008; 68: 3077-3080
        • Hanahan D.
        • Weinberg R.A.
        Hallmarks of cancer: the next generation.
        Cell. 2011; 144: 646-674
        • Lim B.
        • Woodward W.A.
        • Wang X.
        • Reuben J.M.
        • Ueno N.T.
        Inflammatory breast cancer biology: the tumour microenvironment is key.
        Nat Rev Cancer. 2018; 18: 485-499
        • Duan J.
        • Wang Y.
        • Jiao S.
        Checkpoint blockade-based immunotherapy in the context of tumor microenvironment: Opportunities and challenges.
        Cancer Med. 2018; 7: 4517-4529
        • Son B.
        • Lee S.
        • Youn H.
        • Kim E.
        • Kim W.
        • Youn B.
        The role of tumor microenvironment in therapeutic resistance.
        Oncotarget. 2016; 8: 3933-3945
        • Slastnikova T.A.
        • Ulasov A.V.
        • Rosenkranz A.A.
        • Sobolev A.S.
        Targeted intracellular delivery of antibodies: the state of the art.
        Front Pharmacol. 2018; 9: 1208
        • Adams D.
        • Gonzalez-Duarte A.
        • O'Riordan W.D.
        • Yang C.-C.
        • Ueda M.
        • Kristen A.V.
        • et al.
        Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis.
        N Engl J Med. 2018; 379: 11-21
        • Ledford H.
        Gene-silencing technology gets first drug approval after 20-year wait.
        Nature. 2018; 560: 291-292
        • Reinert T.
        • Barrios C.H.
        Optimal management of hormone receptor positive metastatic breast cancer in 2016.
        Ther Adv Med Oncol. 2015; 7: 304-320
        • D'Souza A.
        • Spicer D.
        • Lu J.
        Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer.
        J Hematol Oncol. 2018; 11: 80
        • Caswell-Jin J.L.
        • Plevritis S.K.
        • Tian L.
        • et al.
        Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review.
        JNCI Cancer Spectr. 2018; 2pky062
        • Pernas S.
        • Tolaney S.M.
        • Winer E.P.
        • Goel S.
        CDK4/6 inhibition in breast cancer: current practice and future directions.
        Ther Adv Med Oncol. 2018; 101758835918786451
        • Burstein H.J.
        The distinctive nature of HER2-positive breast cancers.
        N Engl J Med. 2005; 353: 1652-1654
        • Rexer B.N.
        • Arteaga C.L.
        Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications.
        Crit Rev Oncog. 2012; 17: 1-16
        • Cooke T.
        • Reeves J.
        • Lanigan A.
        • Stanton P.
        HER2 as a prognostic and predictive marker for breast cancer.
        Ann Oncol. 2001; 12: S23-S28
        • Seidman A.D.
        • Fornier M.N.
        • Esteva F.J.
        • et al.
        Weekly Trastuzumab and Paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification.
        J Clin Oncol. 2001; 19: 2587-2595
        • Blackwell K.L.
        • Burstein H.J.
        • Storniolo A.M.
        • et al.
        Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.
        J Clin Oncol. 2012; 30: 2585-2592
        • Blackwell K.L.
        • Burstein H.J.
        • Storniolo A.M.
        • et al.
        Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer.
        J Clin Oncol. 2010; 28: 1124-1130
        • Saura C.
        • Garcia-Saenz J.A.
        • Xu B.
        • et al.
        Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2–positive breast cancer.
        J Clin Oncol. 2014; 32: 3626-3633
        • Baselga J.
        • Cortes J.
        • Kim S.B.
        • et al.
        Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.
        N Engl J Med. 2012; 366: 109-119
        • Ellis P.A.
        • Barrios C.H.
        • Eiermann W.
        • et al.
        Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs trastuzumab + taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study.
        J Clin Oncol. 2015; 33 (2015 ASCO Annual Meeting): 507
        • Bauer K.R.
        • Brown M.
        • Cress R.D.
        • Parise C.A.
        • Caggiano V.
        Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry.
        Cancer. 2007; 109: 1721-1728
        • Cheang M.C.U.
        • Voduc D.
        • Bajdik C.
        • Leung S.
        • McKinney S.
        • Chia S.K.
        • et al.
        Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.
        Clin Cancer Res. 2008; 14: 1368-1376
        • Kennecke H.
        • Yerushalmi R.
        • Woods R.
        • et al.
        Metastatic behavior of breast cancer subtypes.
        J Clin Oncol. 2010; 28: 3271-3277
      1. Atezolizumab combo approved for PD-L1–positive TNBC.
        Cancer Discov. 2019; 9 (OF2)
        • Schmid P.
        • Adams S.
        • Rugo H.S.
        • et al.
        Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
        N Engl J Med. 2018; 379: 2108-2121
        • Bernards R.
        [The Nobel Prize in Physiology or Medicine for 2006 for the discovery of RNA interference].
        Ned Tijdschr Geneeskd. 2006; 150: 2849-2853
      2. Comprehensive molecular portraits of human breast tumours.
        Nature. 2012; 490: 61-70
        • Hopkins A.L.
        • Groom C.R.
        The druggable genome.
        Nat Rev Drug Discov. 2002; 1: 727-730
        • Wang J.
        • Lu Z.
        • Wientjes M.G.
        • Au J.L.S.
        Delivery of siRNA therapeutics: barriers and carriers.
        AAPS J. 2010; 12: 492-503
        • Choi H.S.
        • Liu W.
        • Misra P.
        • et al.
        Renal clearance of quantum dots.
        Nat Biotechnol. 2007; 25: 1165-1170
        • Zatsepin T.S.
        • Kotelevtsev Y.V.
        • Koteliansky V.
        Lipid nanoparticles for targeted siRNA delivery - going from bench to bedside.
        Int J Nanomed. 2016; 11: 3077-3086
        • Sinn P.L.
        • Sauter S.L.
        • McCray Jr, PB
        Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors–design, biosafety, and production.
        Gene Ther. 2005; 12: 1089-1098
        • Davis M.E.
        • Zuckerman J.E.
        • Choi C.H.J.
        • et al.
        Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles.
        Nature. 2010; 464: 1067-1070
        • Zuckerman J.E.
        • Choi C.H.J.
        • Han H.
        • Davis M.E.
        Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane.
        Proc Natl Acad Sci. 2012; 109: 3137-3142
        • Zuckerman J.E.
        • Gritli I.
        • Tolcher A.
        • et al.
        Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA.
        Proc Natl Acad Sci. 2014; 111: 11449-11454
        • Lorenzer C.
        • Dirin M.
        • Winkler A.M.
        • Baumann V.
        • Winkler J.
        Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics.
        J Control Release. 2015; 203: 1-15
        • Akinc A.
        • Goldberg M.
        • Qin J.
        • et al.
        Development of lipidoid-siRNA formulations for systemic delivery to the liver.
        Mol Ther. 2009; 17: 872-879
        • Liu F.
        • Liu D.
        Serum independent liposome uptake by mouse liver.
        Biochim Biophys Acta. 1996; 1278: 5-11
        • Greish K.
        Enhanced permeability and retention (EPR) effect for anticancer nanomedicine drug targeting.
        Methods Mol Biol. 2010; 624: 25-37
        • Maeda H.
        Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity.
        Adv Drug Deliv Rev. 2015; 91: 3-6
        • Ngamcherdtrakul W.
        • Castro D.J.
        • Gu S.
        • et al.
        Current development of targeted oligonucleotide-based cancer therapies: perspective on HER2-positive breast cancer treatment.
        Cancer Treat Rev. 2016; 45: 19-29
        • Redig A.J.
        • McAllister S.S.
        Breast cancer as a systemic disease: a view of metastasis.
        J Intern Med. 2013; 274: 113-126
        • Hagemeister Jr., FB
        • Buzdar A.U.
        • Luna M.A.
        • Blumenschein G.R.
        Causes of death in breast cancer: a clinicopathologic study.
        Cancer. 1980; 46: 162-167
        • Morry J.
        • Ngamcherdtrakul W.
        • Yantasee W.
        Oxidative stress in cancer and fibrosis: opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles.
        Redox Biol. 2017; 11: 240-253
        • Jin X.
        • Mu P.
        Targeting breast cancer metastasis.
        Breast Cancer. 2015; 9 (BCBCR.S25460): 23-34
        • de Groot A.E.
        • Roy S.
        • Brown J.S.
        • Pienta K.J.
        • Amend S.R.
        Revisiting seed and soil: examining the primary tumor and cancer cell foraging in metastasis.
        Mol Cancer Res. 2017; 15: 361-370
        • Nguyen L.K.
        • Matallanas D.
        • Croucher D.R.
        • von Kriegsheim A.
        • Kholodenko B.N.
        Signalling by protein phosphatases and drug development: a systems-centred view.
        FEBS J. 2013; 280: 751-765
        • Hurtley S.M.
        Drugging the undruggable.
        Science. 2018; 361: 1084-1085
        • Zhang Z.Y.
        Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases.
        Acc Chem Res. 2017; 50: 122-129
        • Pavan S.
        • Meyer-Schaller N.
        • Diepenbruck M.
        • Kalathur R.K.R.
        • Saxena M.
        • Christofori G.
        A kinome-wide high-content siRNA screen identifies MEK5–ERK5 signaling as critical for breast cancer cell EMT and metastasis.
        Oncogene. 2018; 37: 4197-4213
        • Parmar M.B.
        • Meenakshi Sundaram D.N.
        • K C R.
        • Maranchuk R.
        • Montazeri Aliabadi H.
        • Hugh J.C.
        • et al.
        Combinational siRNA delivery using hyaluronic acid modified amphiphilic polyplexes against cell cycle and phosphatase proteins to inhibit growth and migration of triple-negative breast cancer cells.
        Acta Biomater. 2018; 66: 294-309
        • Ell B.
        • Kang Y.
        Transcriptional control of cancer metastasis.
        Trends Cell Biol. 2013; 23: 603-611
        • Yan C.
        • Higgins P.J.
        Drugging the undruggable: transcription therapy for cancer.
        Biochim Biophys Acta. 2013; 1835: 76-85
        • Yu H.
        • Guo C.
        • Feng B.
        • et al.
        Triple-layered pH-responsive micelleplexes loaded with siRNA and cisplatin prodrug for NF-Kappa B targeted treatment of metastatic breast cancer.
        Theranostics. 2016; 6: 14-27
        • Tang S.
        • Yin Q.
        • Su J.
        • et al.
        Inhibition of metastasis and growth of breast cancer by pH-sensitive poly (beta-amino ester) nanoparticles co-delivering two siRNA and paclitaxel.
        Biomaterials. 2015; 48: 1-15
        • Xu C.
        • Zhao H.
        • Chen H.
        • Yao Q.
        CXCR4 in breast cancer: oncogenic role and therapeutic targeting.
        Drug Des Devel Ther. 2015; 9: 4953-4964
        • Mukherjee D.
        • Zhao J.
        The Role of chemokine receptor CXCR4 in breast cancer metastasis.
        Am J Cancer Res. 2013; 3: 46-57
        • Zhou Y.
        • Yu F.
        • Zhang F.
        • et al.
        Cyclam-modified PEI for combined VEGF siRNA silencing and CXCR4 inhibition to treat metastatic breast cancer.
        Biomacromolecules. 2018; 19: 392-401
        • Guo P.
        • You J.-O.
        • Yang J.
        • Jia D.
        • Moses M.A.
        • Auguste D.T.
        Inhibiting metastatic breast cancer cell migration via the synergy of targeted, pH-triggered siRNA delivery and chemokine axis blockade.
        Mol Pharm. 2014; 11: 755-765
        • Vaidya A.M.
        • Sun Z.
        • Ayat N.
        • et al.
        Systemic delivery of tumor-targeting siRNA nanoparticles against an oncogenic LncRNA facilitates effective triple-negative breast cancer therapy.
        Bioconjug Chem. 2019; 30: 907-919
        • Morry J.
        • Ngamcherdtrakul W.
        • Gu S.
        • et al.
        Targeted treatment of metastatic breast cancer by PLK1 siRNA delivered by an antioxidant nanoparticle platform.
        Mol Cancer Ther. 2017; 16: 763-772
        • Chio IIC
        • Tuveson D.A.
        ROS in cancer: the burning question.
        Trends Mol Med. 2017; 23: 411-429
        • Quintavalle M.
        • Elia L.
        • Price J.H.
        • Heynen-Genel S.
        • Courtneidge S.A.
        A cell-based high-content screening assay reveals activators and inhibitors of cancer cell invasion.
        Sci Signal. 2011; 4 (ra49)
        • Meng H.
        • Mai W.X.
        • Zhang H.
        • et al.
        Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo.
        ACS Nano. 2013; 7: 994-1005
        • Deng Z.J.
        • Morton S.W.
        • Ben-Akiva E.
        • Dreaden E.C.
        • Shopsowitz K.E.
        • Hammond P.T.
        Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment.
        ACS Nano. 2013; 7: 9571-9584
        • Gong C.
        • Hu C.
        • Gu F.
        • et al.
        Co-delivery of autophagy inhibitor ATG7 siRNA and docetaxel for breast cancer treatment.
        J Control Release. 2017; 266: 272-286
        • Wang S.
        • Liu X.
        • Chen S.
        • et al.
        Regulation of Ca2+ signaling for drug-resistant breast cancer therapy with mesoporous silica nanocapsule encapsulated doxorubicin/siRNA cocktail.
        ACS Nano. 2019; 13: 274-283
        • Yu S.
        • Chen Y.
        • Li X.
        • Gao Z.
        • Liu G.
        Chitosan nanoparticle-delivered siRNA reduces CXCR4 expression and sensitizes breast cancer cells to cisplatin.
        Biosci Rep. 2017; 37BSR20170122
        • Yang L.
        • Tian Y.
        • Leong W.S.
        • et al.
        Efficient and tumor-specific knockdown of MTDH gene attenuates paclitaxel resistance of breast cancer cells both in vivo and in vitro.
        Breast Cancer Res. 2018; 20: 113
        • Ngamcherdtrakul W.
        • Morry J.
        • Gu S.
        • et al.
        Cationic polymer modified mesoporous silica nanoparticles for targeted siRNA delivery to HER2+ breast cancer.
        Adv Funct Mater. 2015; 25: 2646-2659
        • Gu S.
        • Hu Z.
        • Ngamcherdtrakul W.
        • et al.
        Therapeutic siRNA for drug-resistant HER2-positive breast cancer.
        Oncotarget. 2016; 7: 14727-14741
        • Gu S.
        • Ngamcherdtrakul W.
        • Reda M.
        • Hu Z.
        • Gray J.W.
        • Yantasee W.
        Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment.
        PLoS One. 2018; 13e0198141
        • Binnewies M.
        • Roberts E.W.
        • Kersten K.
        • et al.
        Understanding the tumor immune microenvironment (TIME) for effective therapy.
        Nat Med. 2018; 24: 541-550
        • Qiu S.-Q.
        • Waaijer S.J.H.
        • Zwager M.C.
        • de Vries E.G.E.
        • van der Vegt B.
        • Schröder C.P.
        Tumor-associated macrophages in breast cancer: innocent bystander or important player?.
        Cancer Treat Rev. 2018; 70: 178-189
        • Song Y.
        • Tang C.
        • Yin C.
        Combination antitumor immunotherapy with VEGF and PIGF siRNA via systemic delivery of multi-functionalized nanoparticles to tumor-associated macrophages and breast cancer cells.
        Biomaterials. 2018; 185: 117-132
        • Shen S.
        • Zhang Y.
        • Chen K.G.
        • Luo Y.L.
        • Wang J.
        Cationic polymeric nanoparticle delivering CCR2 siRNA to inflammatory monocytes for tumor microenvironment modification and cancer therapy.
        Mol Pharm. 2018; 15: 3642-3653
        • Su S.
        • Liao J.
        • Liu J.
        • Huang D.
        • et al.
        Blocking the recruitment of naive CD4(+) T cells reverses immunosuppression in breast cancer.
        Cell Res. 2017; 27: 461-482
        • Wu Y.
        • Gu W.
        • Li J.
        • Chen C.
        • Xu Z.P.
        Silencing PD-1 and PD-L1 with nanoparticle-delivered small interfering RNA increases cytotoxicity of tumor-infiltrating lymphocytes.
        Nanomedicine. 2019; 14: 955-967
        • Allard B.
        • Longhi M.S.
        • Robson S.C.
        • Stagg J.
        The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets.
        Immunol Rev. 2017; 276: 121-144
        • Jadidi-Niaragh F.
        • Atyabi F.
        • Rastegari A.
        • et al.
        CD73 specific siRNA loaded chitosan lactate nanoparticles potentiate the antitumor effect of a dendritic cell vaccine in 4T1 breast cancer bearing mice.
        J Control Release. 2017; 246: 46-59
        • Zhang M.
        • Yan L.
        • Kim J.A.
        Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment.
        Cancer Gene Ther. 2015; 22: 463-474
        • Cassetta L.
        • Pollard J.W.
        Targeting macrophages: therapeutic approaches in cancer.
        Nat Rev Drug Discov. 2018; 17: 887
        • Samanta D.
        • Park Y.
        • Ni X.
        • et al.
        Chemotherapy induces enrichment of CD47+/CD73+/PDL1+ immune evasive triple-negative breast cancer cells.
        Proc Natl Acad Sci. 2018; 115: E1239-E1E48

      Linked Article