Gene Knockdown by EpCAM Aptamer-siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells.
Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer-siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM(+) cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro TIC assays) and tumor initiation by EpCAM(+) luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM(-) mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM(+) Her2(+) and TNBC tumors and suppress their growth. Thus, EpCAM-AsiCs provide an attractive approach for treating epithelial cancer.
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Adi
A
Gilboa-Geffen
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
Peter
P
Hamar
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Minh T N
MT
Le
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Lee Adam
LA
Wheeler
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Radiana
R
Trifonova
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Fabio
F
Petrocca
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Anders
A
Wittrup
Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. judy.lieberman@childrens.harvard.edu.
Judy
J
Lieberman
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D000097869:Polo-Like Kinase 1
D000951:Antigens, Neoplasm; D052157:Aptamers, Nucleotide; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D000071858:Epithelial Cell Adhesion Molecule; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1; C499379:EPCAM protein, human