Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice

Amy Brock, Silva Krause, Hu Li, Marek Kowalski, Michael S. Goldberg, James J. Collins, Donald E. Ingber

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

With advances in screening, the incidence of detection of premalignant breast lesions has increased in recent decades; however, treatment options remain limited to surveillance or surgical removal by lumpectomy or mastectomy. We hypothesized that disease progression could be blocked by RNA interference (RNAi) therapy and set out to develop a targeted therapeutic delivery strategy. Using computational gene network modeling, we identified HoxA1 as a putative driver of early mammary cancer progression in transgenic C3(1)-SV40TAg mice. Silencing this gene in cultured mouse or human mammary tumor spheroids resulted in increased acinar lumen formation, reduced tumor cell proliferation, and restoration of normal epithelial polarization.When the HoxA1 gene was silenced in vivo via intraductal delivery of nanoparticle-formulated small interfering RNA (siRNA) through the nipple of transgenic mice with early-stage disease,mammary epithelial cell proliferation rates were suppressed, loss of estrogen and progesterone receptor expression was prevented, and tumor incidencewas reduced by 75%. This approach that leverages new advances in systems biology and nanotechnology offers a novel noninvasive strategy to block breast cancer progression through targeted silencing of critical genes directly within the mammary epithelium.

Original languageEnglish (US)
Article number217ra2
JournalScience Translational Medicine
Volume6
Issue number217
DOIs
StatePublished - Jan 1 2014

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Nanoparticles
Small Interfering RNA
Breast
Gene Silencing
Breast Neoplasms
Injections
Cell Proliferation
Nanotechnology
Systems Biology
Segmental Mastectomy
Nipples
Gene Regulatory Networks
Mastectomy
Progesterone Receptors
RNA Interference
Estrogen Receptors
Transgenic Mice
Disease Progression
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. / Brock, Amy; Krause, Silva; Li, Hu; Kowalski, Marek; Goldberg, Michael S.; Collins, James J.; Ingber, Donald E.

In: Science Translational Medicine, Vol. 6, No. 217, 217ra2, 01.01.2014.

Research output: Contribution to journalArticle

Brock, Amy ; Krause, Silva ; Li, Hu ; Kowalski, Marek ; Goldberg, Michael S. ; Collins, James J. ; Ingber, Donald E. / Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice. In: Science Translational Medicine. 2014 ; Vol. 6, No. 217.
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