Significance of Inhibiting Long Non-coding RNAs in Advanced Breast Cancer

三阴性乳腺癌（TNBC）亚型患者的临床现实是严峻的，因为 对针对雌激素受体（ER）或人表皮生长因子的靶向治疗缺乏反应 受体2（HER 2）。此外，TNBC的转移率、复发率和死亡率都有所增加。 TNBC的常见转移部位包括肺、骨、肝、胸膜和脑。特别感兴趣的 是乳腺癌脑转移（BCBM），因为它占在乳腺癌中观察到的转移性疾病的约15%。 乳腺癌患者，但平均存活时间仅为4至6个月。脑转移 是TNBC患者中甚至更常见的特征，发病率高达20- 50%。现 BCBM患者只能选择姑息治疗，主要是因为难以确定 脑转移性病变发展的分子基础。在我们的初步研究中，我们已经采取了初步的 确定巴塞尔公约建立信任措施科学基础的步骤。我们的初步数据表明， RNA（lncRNA）Lnc-BM显示乳腺癌患者脑转移发展的预测潜力。 此外，我们的临床前模型表明，Lnc-BM表达水平升高导致乳腺癌发生率增加。 Lnc-BM基因敲低可显著抑制脑转移瘤的发生， 转移 该提案的中心假设是Lnc-BM触发JAK 2/STAT 3通路的激活 促进乳腺癌脑转移，这可以通过SiRNA的纳米颗粒递送在体内减弱。 将根据以下具体目标处理这一假设。具体目标1： 证明了Lnc-BM和JAK 2/STAT 3通路在促进乳腺癌脑转移中的功能作用。 转移在具体目标2中，我们将展示促进Lnc-BM依赖性 JAK 2过度激活。在具体目标3中，我们将确定是否使用NP递送的siRNA靶向Lnc-BM， 可有效抑制异种移植模型中脑转移病灶的发展。 通过使用小鼠模型，该提案将通过递送抗-Lnc-BM来评估Lnc-BM的生物学意义。 Lnc-BM siRNA使用纳米颗粒穿过血脑屏障（BBB），并通过评估其减少 体内Lnc-BM水平以及脑转移病灶的程度。如果进一步发展，Lnc-BM可能会证明 可用于早期识别具有发生脑转移风险增加的乳腺癌患者 病变尽管需要更多的研究来验证Lnc-BM在脑中的参与程度， 在TNBC患者的转移潜力中，预后筛选标志物将改善早期检测， 甚至是预防。

The clinical reality for patients with the triple-negative breast cancer (TNBC) subtype is grim because of a lack of response to targeted therapies against the estrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). Furthermore, TNBC presents with increased rates of metastasis, relapse, and mortality. Common sites of metastasis for TNBC include the lung, bone, liver, pleura, and the brain. Of particular interest is breast cancer brain metastasis (BCBM) because it accounts for about 15% of metastatic disease observed in breast cancer patients but have poor median survival times that are only between 4 to 6 months. Brain metastasis is an even more common feature in TNBC patients, with incidence rates that reach up to 20-50%. At the present time only palliative options are available for patients with BCBM, primarily because of challenges in determining the molecular basis of brain metastatic lesion development. In our preliminary research, we have taken the initial steps of identifying the scientific underpinnings of BCBM. Our preliminary data indicate that the long non-coding RNA (lncRNA) Lnc-BM shows predictive potential for brain metastatic development in breast cancer patients. Also, our preclinical models demonstrate that elevated Lnc-BM expression levels resulted in increased breast cancer cell metastasis to the brain, while Lnc-BM knockdown drastically inhibited the incidence of brain metastasis. The central hypothesis of the proposal is that Lnc-BM-triggered activation of the JAK2/STAT3 pathway promotes breast cancer brain metastasis, which could be attenuated in vivo by nanoparticle-delivery of siRNAs. The hypothesis will be addressed in accordance to the following specific aims. In Specific Aim 1, we will demonstrate the functional role of Lnc-BM and the JAK2/STAT3 pathway in promoting breast cancer brain metastasis. In Specific Aim 2, we will demonstrate the underlying mechanisms that promote Lnc-BM-dependent JAK2 hyperactivation. In Specific Aim 3, we will determine whether targeting Lnc-BM using NP-delivered siRNAs can effectively inhibit the development of brain metastatic lesions in xenograft models. By using mouse models, the proposal will assess the biological significance of Lnc-BM by delivering anti- Lnc-BM siRNAs across the blood brain barrier (BBB) using nanoparticles and by evaluating its ability to diminish Lnc-BM levels in vivo as well as the extent of brain metastatic lesions. If further developed, Lnc-BM may prove useful in early identification of breast cancer patients who are at increased risk for developing brain metastatic lesions. Although additional studies will be required to validate the degree of Lnc-BM involvement in brain metastatic potential in TNBC patients, a prognostic screening marker would improve early detection and perhaps even prevention.