Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells

Adi Gilboa-Geffen, P. Hamar, Minh T N Le, Lee Adam Wheeler, Radiana Trifonova, Fabio Petrocca, Anders Wittrup, Judy Lieberman

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2279-2291
Number of pages13
JournalMolecular Cancer Therapeutics
Volume14
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

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Gene Knockdown Techniques
Neoplastic Stem Cells
Small Interfering RNA
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Epithelial Cell Adhesion Molecule
Neoplasm Antigens
RNA Interference
Nude Mice
Biopsy
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells. / Gilboa-Geffen, Adi; Hamar, P.; Le, Minh T N; Wheeler, Lee Adam; Trifonova, Radiana; Petrocca, Fabio; Wittrup, Anders; Lieberman, Judy.

In: Molecular Cancer Therapeutics, Vol. 14, No. 10, 01.10.2015, p. 2279-2291.

Research output: Contribution to journalArticle

Gilboa-Geffen, A, Hamar, P, Le, MTN, Wheeler, LA, Trifonova, R, Petrocca, F, Wittrup, A & Lieberman, J 2015, 'Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells', Molecular Cancer Therapeutics, vol. 14, no. 10, pp. 2279-2291. https://doi.org/10.1158/1535-7163.MCT-15-0201-T
Gilboa-Geffen, Adi ; Hamar, P. ; Le, Minh T N ; Wheeler, Lee Adam ; Trifonova, Radiana ; Petrocca, Fabio ; Wittrup, Anders ; Lieberman, Judy. / Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 10. pp. 2279-2291.
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