Elucidate the role of miR-141 in brain metastasis from breast cancer

描述(申请人提供)：乳腺癌的治疗已取得重大进展；然而，脑转移患者的预后仍然很差，生存时间极短。高达30%的晚期乳腺癌患者会发生脑转移，这类患者的管理策略仍然是一个主要的临床挑战。寻找预防和治疗脑转移的新疗法需要了解脑转移的生物学和分子基础，目前这一点受到缺乏实验模型和特定治疗靶点的限制。我们最近开发了两个炎症性乳腺癌(IBC)细胞株尾静脉注射导致高脑转移率(67%)的小鼠模型，比以前的异种移植模型有了实质性的改善。值得注意的是，miR-141是一种我们发现在IBC细胞系和患者样本中过度表达的microRNA，它特异性地阻止了脑转移，而不影响肺转移。我们还从脑转移瘤中产生了克隆，与肺转移瘤来源的克隆相比，miR-141的表达非常高。然而，目前尚不清楚miR-141是否足以通过尾静脉注射所有乳腺癌细胞株产生高转移率，也不清楚miR-14的调节如何阻止脑转移。这里提出的工作目的是解决这样的假设，即miR-141在促进脑转移定植方面具有重要作用，并可以作为预防脑转移的可行靶点。目标1下的研究将确定miR-141是否介导了广泛的IBC和非IBC细胞系的脑转移，以及miR-141是否足以通过尾静脉注射到小鼠体内种植转移瘤。目的2将利用我们独特的体内和体外脑转移模型，确定miR-141抑制如何显着抑制脑转移定植的机制见解，并确定治疗靶点。我们将在我们的异种移植模型中进一步测试系统应用反义miR-141预防和治疗脑转移的治疗效果。这项拟议的研究与公共卫生相关，因为它有可能确定新的靶点，开发新的策略来预防和治疗乳腺癌的脑转移，从而改善乳腺癌患者的预后。

DESCRIPTION (provided by applicant): Significant advances have been achieved in the treatment of breast cancer; however, the prognosis for patients with brain metastasis remains dismal, with extremely short survival times. Up to 30% of patients with advanced breast cancer develop brain metastases, and management strategies for such patients continue to be a major clinical challenge. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of brain metastasis, which currently is constrained by a dearth of experimental models and specific therapeutic targets. We recently developed mouse models in which tail-vein injection of two inflammatory breast cancer (IBC) cell lines led to a high rate of brain metastasis (67%), a substantial improvement over previous xenograft models. Notably, knockdown of miR-141, a microRNA we found to be overrepresented in IBC cell lines and patient samples, specifically blocked brain metastasis without affecting lung metastasis. We also generated clones from the brain metastases that showed very high expression of miR-141 compared with lung metastasis-derived clones. However, it is unknown whether miR-141 is sufficient to generate a high rate of brain metastasis via tail-vein injection of all breast cancer cell lines, and it is unclear how modulation of miR-14 blocks brain metastasis. The aims of the work proposed here address the hypothesis that miR-141 has a significant role in promoting metastatic colonization to the brain and can serve as a viable target for prevention of brain metastasis. Studies under Aim 1 will determine if miR-141 mediates brain metastasis of a broad range of IBC and non-IBC cell lines and whether miR-141 is sufficient for metastasis seeding via tail vein injection into mice. Aim 2 will identify mechanitic insights into how miR-141 inhibition significantly suppresses brain metastatic colonization and identify therapeutic targets taking advantage of our unique in vivo and in vitro brain metastasis models. We will further test the therapeutic efficacy of systemically administered anti-sense miR-141 in the prevention and treatment of brain metastases in our xenograft models. The proposed research is relevant to public health because it has the potential to identify novel targets and develop novel strategies to prevent and treat brain metastasis from breast cancer and thereby improve outcomes for patients with breast cancer.