Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice.
Silencing HoxA1 by intraductal injection of siRNA lipidoid nanoparticles prevents mammary tumor progression in mice.
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DOI：
10.1126/scitranslmed.3007048
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发表时间：
2014-01-01
影响因子：
17.1
通讯作者：
Ingber DE
中科院分区：
文献类型：
--
作者：
Brock A;Krause S;Li H;Kowalski M;Goldberg MS;Collins JJ;Ingber DE
随着筛查技术的进步，近几十年来乳腺癌前病变的检出率有所增加;然而，治疗选择仍限于监测或通过乳房肿瘤切除术或乳房切除术进行手术切除。我们假设疾病进展可以通过RNA干扰（RNAi）治疗来阻断，并着手开发靶向治疗药物递送策略。使用计算基因网络建模，我们确定HoxA 1作为转基因C3-SV 40 TAg小鼠早期乳腺癌进展的假定驱动因素。在培养的小鼠或人乳腺肿瘤球体中沉默该基因导致腺泡腔形成增加，肿瘤细胞增殖减少，并恢复正常上皮极化。当HoxA 1基因在体内通过导管内递送纳米颗粒配制的小干扰RNA（siRNA）通过具有早期疾病的转基因小鼠的乳头沉默时，乳腺上皮细胞增殖率被抑制，雌激素和孕激素受体表达的丧失被阻止，并且肿瘤发病率降低了75%。这种利用系统生物学和纳米技术新进展的方法提供了一种新的非侵入性策略，通过直接在乳腺上皮内靶向沉默关键基因来阻断乳腺癌进展。
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-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 proliferate rates were suppressed, loss of estrogen and progesterone receptor expression was prevented, and tumor incidence was reduced by 75%. This approach that leverages new advances in systems biology and nanotechnology offers a novel non-invasive strategy to block breast cancer progression through targeted silencing of critical genes directly within the mammary epithelium.
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影响因子：
0.9
作者：
Flanagan, Meghan;Love, Susan;Hwang, E Shelley
通讯作者：
Hwang, E Shelley
影响因子：
3.3
作者：
Love, Susan M.;Zhang, Wei;Zhang, Baoning
通讯作者：
Zhang, Baoning
DOI：
10.1158/1078-0432.ccr-12-0373
发表时间：
2012-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chen JL;Li J;Kiriluk KJ;Rosen AM;Paner GP;Antic T;Lussier YA;Vander Griend DJ
通讯作者：
Vander Griend DJ
DOI：
10.1186/bcr1798
发表时间：
2007
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dowsett M;Goldhirsch A;Hayes DF;Senn HJ;Wood W;Viale G
通讯作者：
Viale G
DOI：
10.3791/50692
发表时间：
2013-10-04
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Krause S;Brock A;Ingber DE
通讯作者：
Ingber DE