Systemic delivery of miR-29 for basal-like breast cancer treatment

ABSTACT 基底样癌是雌激素受体(ER)、孕激素受体(PR)和Her2阴性；它是 对荷尔蒙治疗和针对HER2蛋白的药物没有反应。因此，迫切需要发展。 基底细胞样乳腺癌的新治疗策略。基底细胞样乳腺癌富含肿瘤起始细胞。 肿瘤起始细胞是癌症转移和复发的驱动力；因此，靶向肿瘤起始细胞是 对于基底样乳腺癌的治疗至关重要。我们最近的研究表明，3WJ RNA纳米颗粒 与EGFR适配子成功结合并进入基底样乳腺癌细胞系MDA- MB-231在培养和原位小鼠乳腺肿瘤模型中的表达。靶向肿瘤的RNA适配子 启动细胞标志物CD44已被鉴定和鉴定，这为临床治疗提供了一种潜在的策略 将三向连接(3WJ)RNA纳米颗粒输送到肿瘤起始细胞。我们和其他人最近 证明miR-29b是治疗基底细胞样乳腺癌的有效肿瘤抑制因子。外源基因的表达 基底样乳腺癌细胞系中的MIR-29b显著抑制原位乳腺癌细胞的转移 3D培养中的肿瘤模型和抑制的恶性表型。MIR-29也显示出强大的抑制作用 肿瘤启动细胞的活性。因此，我们预测miR-29b的治疗性传递将抑制基底样蛋白。 乳腺癌的进展和转移。这项提议的总体目标是开发一部小说 以治疗性方式将抑癌基因miRNA导入基底细胞样乳腺癌的方法。在与 针对基底细胞样乳腺癌细胞表面标志的RNA适配子和增强的2‘F修饰 MiRNA稳定性，RNA纳米颗粒为治疗性地将miR-29输送到类基底细胞提供了强大的工具 乳腺癌。这一提议的中心假设是肿瘤抑制基因miR-29b可以是 使用3WJ RNA纳米粒治疗基底样乳腺癌组织，并随后 抑制癌症的进展和转移。来检验我们的中心假设并实现这一目标 建议，我们设计了具有以下具体目标的实验。目的1.构建RNA 含有治疗性miR-29b的纳米颗粒将靶向基底样乳腺癌细胞。目标2. 多功能治疗性RNA纳米粒在小鼠体内的生物活性研究 乳腺肿瘤模型。向基底样癌转移miR-29b的RNA纳米粒的研究进展 组织和肿瘤启动细胞将克服目前利用miRNA进行癌症治疗的障碍。 检测外源性miR-29b对基底样癌进展和转移的抑制作用 癌症可能会为这种致命疾病找到一种潜在的治疗策略。

ABSTACT Basal-like breast cancer is estrogen receptor (ER), progesterone receptor (PR) and Her2 negative; it is not responsive to hormone therapy and drugs that target the HER2 protein. Therefore, it is urgent to develop novel therapeutic strategies for basal-like breast cancer. Basal-like breast cancer is rich in tumor-initiating cells. Tumor initiating cells are drivers of cancer metastasis and relapses; thus targeting tumor-initiating cells is critical for basal-like breast cancer treatment. Our recent study shows that 3WJ RNA nanoparticles incorporated with EGFR aptamer successfully bind and enter into the basal-like breast cancer cell line MDA- MB 231 in culture and in the orthotopic mouse mammary tumor model. RNA aptamers targeting the tumor initiating cell marker CD44 have been identified and characterized, which offers a potential strategy for delivering the 3-way junction (3WJ) RNA nanoparticles into tumor initiating cells. We and others recently demonstrate that miR-29b is a potent tumor suppressor for basal-like breast cancer. Expression of exogenous miR-29b in basal-like breast cancer cell lines significantly inhibits cancer metastasis in orthotopic mammary tumor models and repressed malignant phenotypes in 3D culture. MiR-29 also demonstrate potent inhibitory activity on tumor-initiating cells. Therefore, we predict that therapeutic delivery of miR-29b will inhibit basal-like breast cancer progression and metastasis. The overall objective of this proposal is to develop a novel approach to therapeutically deliver tumor suppressor miRNA into basal-like breast cancer. In combining with RNA aptamers to target cell surface markers of basal-like breast cancer and 2’F modification to enhance miRNA stability, the RNA nanoparticle provides a powerful tool to therapeutically deliver miR-29 to basal-like breast cancer. The central hypothesis of this proposal is that tumor suppressor miR-29b can be therapeutically delivered to basal-like breast cancer tissue using 3WJ RNA nanoparticles, and subsequently represses cancer progression and metastasis. To test our central hypothesis and achieve the objective of this proposal, we have designed experiments with the following specific aims. Aim 1. Construct RNA nanoparticles harboring therapeutic miR-29b that will target basal-like breast cancer cells. Aim 2. Examine the biologic activity of multifunctional therapeutic RNA nanoparticles in the orthotopic mouse mammary tumor model. Development of RNA nanoparticles that deliver miR-29b to basal-like breast cancer tissue and tumor-initiating cells will overcome the current hurdle in utilizing miRNA for cancer therapy. Examining the potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breast cancer may identify a potential therapeutic strategy for this deadly disease.