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

描述（由申请人提供）：在乳腺癌的治疗方面已经取得了重大进展;然而，脑转移患者的预后仍然令人沮丧，生存时间极短。高达30%的晚期乳腺癌患者发生脑转移，对此类患者的管理策略仍然是一个重大的临床挑战。寻找预防和治疗脑转移瘤的新疗法需要了解脑转移瘤的生物学和分子基础，目前这受到缺乏实验模型和特定治疗靶点的限制。我们最近开发了小鼠模型，其中尾静脉注射两种炎性乳腺癌（IBC）细胞系导致高脑转移率（67%），比以前的异种移植模型有实质性改善。值得注意的是，我们发现miR-141（一种在IBC细胞系和患者样本中过度表达的microRNA）的敲低特异性阻断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，与肺转移瘤衍生的克隆相比，这些克隆显示出非常高的miR-141表达。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系产生高的脑转移率，也不清楚miR-14的调节如何阻断脑转移。本文提出的工作的目的是解决以下假设：miR-141在促进脑转移定植方面具有重要作用，并且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中进行转移接种。目的2将确定miR-141抑制如何显著抑制脑转移定植的机制见解，并利用我们独特的体内和体外脑转移模型确定治疗靶点。我们将在我们的异种移植模型中进一步测试全身施用反义miR-141在预防和治疗脑转移中的治疗功效。这项拟议的研究与公共卫生有关，因为它有可能确定新的靶点，并开发新的策略来预防和治疗乳腺癌脑转移，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.