Identification of novel prognostic markers in triple-negative breast cancers in African American Women

项目摘要 三阴性乳腺癌（TNBC）的特征在于缺乏雌激素受体（ER）的表达， 孕酮受体（PR）和人表皮生长因子受体2（HER2）。可用 用于TNBC的化疗导致有限的功效和显著的毒性。大多数患者 转移性疾病不能存活超过3年。目前，没有靶向疗法可用于TNBC， 部分原因是它是一种高度异质性的疾病，并且因为TNBC的分子驱动因素尚不清楚。 TNBC更常影响年轻患者（< 50岁），在非裔美国人中的患病率是其两倍 与高加索人相比。有必要了解TNBC的生物学基础基因， 和表观遗传水平，以便能够为个体患者开发靶向治疗。我们已经确定了一 图1显示了可能特异于非裔美国妇女中的TNBC的长非编码RNA（lncRNA）的队列。的 拟议的研究重点是了解这些lncRNA在TNBC中的功能。我们假设 非洲裔美国人中TNBC的差异可以部分解释为非编码基因的表达。 RNA和表观遗传改变是这个群体特有的。我们认为lncRNAs可能在 通过基因调控在该人群中TNBC的启动和进展中起重要作用 表情这一建议由两个具体目标组成，将有力地利用互补的 在信号转导、细胞周期调控、基因表达、细胞周期调控 乳腺癌的临床和治疗在目标1中，我们将检验以下假设： 选择的“驱动lncRNA”将显著影响TNBC细胞增殖、细胞周期进程、存活， 迁移和侵袭。在目标2中，我们建议描述 最有前途的lncRNA使用动物模型，在努力了解他们如何启动和维持 TNBC表型和相关基因表达特征。

Project Summary Triple negative breast cancer (TNBC) is characterized by lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2). Available chemotherapy for TNBC results in limited efficacy and significant toxicity. The majority of patients with metastatic disease do not survive beyond 3 years. Currently, no targeted therapies are available for TNBC, in part because it is a highly heterogeneous disease and because the molecular drivers for TNBC are not known. TNBC more frequently affects younger patients (< 50 years) and is twice as prevalent in African American women as compared to Caucasians. There is a need to understand the biology of TNBC at the basic genetic and epigenetic levels to be able to develop targeted therapies for individual patients. We have identified a cohort of long non-coding RNAs (lncRNAs) that may be specific to TNBC in African American women. The proposed research is focused on understanding the function of these lncRNAs in TNBCs. We hypothesize that disparities in TNBC in the African American population may be explained, in part, by expression of non-coding RNAs and epigenetic alterations that are specific to this population. We propose that lncRNAs may play an important role in the initiation and progression of TNBC in this population through regulation of gene expression. This proposal, consisting of two Specific Aims, will powerfully harness the complementary expertise of a team of investigators with considerable experience in signal transduction, cell cycle control, gene regulation, and clinical aspects of breast cancer. In Aim 1, we will test the hypothesis that down-regulation of selected "driver lncRNAs" will significantly affect TNBC cell proliferation, cell cycle progression, survival, migration, and invasion in TNBC using in vitro models of this disease. In Aim 2, we propose to characterize the most promising lncRNAs using an animal model, in an effort to understand how they initiate and maintain the TNBC phenotype and the associated gene expression signature.