Research ArticleCancer

Silencing HoxA1 by Intraductal Injection of siRNA Lipidoid Nanoparticles Prevents Mammary Tumor Progression in Mice

Science Translational Medicine  01 Jan 2014:
Vol. 6, Issue 217, pp. 217ra2
DOI: 10.1126/scitranslmed.3007048

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Silencing Breast Cancer with Nanoparticle siRNA

Cancer drives researchers crazy. But what drives cancer? In a new study by Brock and colleagues, the researchers modeled the gene network of mice and found HoxA1 to be a putative driver of early breast cancer progression. Silencing this gene using nanoparticle-packaged small interfering RNA (siRNA) led to tumor reduction in mice.

Ductal carcinoma in situ (DCIS) is a noninvasive lesion of the breast that progresses to invasive breast cancer in an estimated 14 to 53% of cases. However, current prognostic methods are unable to predict whether DCIS will indeed become invasive. Brock et al. used a computational gene network inference approach to look at early gene expression changes in mammary tumor progression, and identified HoxA1 as a likely candidate. The authors then confirmed that HoxA1 was overexpressed in human breast lesions by looking at patient gene expression data. To verify the role of this candidate gene in cancer progression, HoxA1 siRNA was formulated into lipidoid nanoparticles and administered to transgenic mice that develop tumors much like people do. The HoxA1-silencing nanoparticles were delivered locally (through the nipple), to avoid any systemic immune response, and led to a decrease in tumor formation, as compared to mice that received control siRNA. Notably, the HoxA1 siRNA prevented the loss of hormone (estrogen and progesterone) receptors in the treated mammary glands—a loss that is one hallmark of breast cancer progression.

This study demonstrates how computational methods can generate viable oncogene candidates for RNA interference (RNAi) therapy. Brock et al. discovered and preliminarily validated HoxA1 as a driver of breast cancer progression in mice, but additional human cell and tissue testing will be needed to verify the role of this gene in human DCIS and mammary tumorigenesis.