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(HER2)。此外，TNBC具有更高的转移率、复发率和死亡率。 TNBC常见的转移部位包括肺、骨、肝、胸膜和脑。特别感兴趣的 乳腺癌脑转移(BCBM)是因为它约占观察到的转移疾病的15% 乳腺癌患者的中位生存期很低，只有4到6个月。脑转移瘤 是TNBC患者中更常见的特征，发病率高达20%-50%。目前 对于BCBM患者来说，只有时间上的缓解选择是可用的，主要是因为在确定 脑转移瘤发生的分子基础。在我们的初步研究中，我们已经采取了初步的 确定BCBM的科学基础的步骤。我们的初步数据表明，长的非编码 RNA(LncRNA)LNC-BM对乳腺癌患者脑转移的发展具有预测潜力。 此外，我们的临床前模型显示，LNC-BM表达水平升高导致乳房增加 肿瘤细胞向脑转移，而LNC-BM基因敲除可显著抑制脑转移的发生 转移。 该提议的中心假设是LNC-BM触发了JAK2/STAT3通路的激活 促进乳腺癌的脑转移，这种转移可以通过纳米siRNAs的体内传递来减弱。 这一假设将根据以下具体目标加以阐述。在具体目标1中，我们将 证明LNC-BM和JAK2/STAT3通路在促进乳腺癌脑功能中的作用 转移。在具体目标2中，我们将演示促进LNC-BM依赖的潜在机制 JAK2的过度激活。在具体目标3中，我们将确定是否使用NP递送的siRNAs靶向LNC-BM 能有效抑制异种移植模型脑转移灶的发展。 通过使用小鼠模型，该提案将评估LNC-BM的生物学意义，通过提供抗 LNC-BM使用纳米颗粒跨越血脑屏障(BBB)的siRNAs，并通过评估其降低 体内LNC-BM水平以及脑转移灶的范围。如果进一步发展，LNC-BM可能会证明 有助于早期识别有脑转移风险的乳腺癌患者 损伤。虽然还需要更多的研究来验证LNC-BM在大脑中的参与程度 TNBC患者的转移潜能，一个预后筛查标记物将改善早期发现，并可能 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.