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)的特征是雌激素受体(ER)缺乏表达， 孕激素受体(PR)和人表皮生长因子受体2(HER2)。可用 TNBC的化疗疗效有限，毒副作用大。大多数患者都患有 转移性疾病的存活期不超过3年。目前，没有针对TNBC的靶向治疗。 部分原因是它是一种高度异质性的疾病，也因为TNBC的分子驱动因素尚不清楚。 TNBC更频繁地影响年轻患者(&lt；50岁)，在非裔美国人中流行两倍 与高加索人相比的女性。有必要从遗传学的基础上了解TNBC的生物学 和表观遗传学水平，能够为个别患者开发有针对性的治疗方法。我们已经确定了一个 非裔美国女性中可能针对TNBC的一组长非编码RNA(LncRNAs)。这个 建议的研究重点是了解这些LncRNAs在TNBCs中的功能。我们假设 非裔美国人群体中TNBC的差异可以部分解释为非编码基因的表达 特定于这一群体的RNA和表观遗传改变。我们认为，lncRNAs可能发挥作用 通过基因调控在该人群TNBC的发生和发展中的重要作用 表情。这项提案由两个具体目标组成，将有力地利用 一支在信号转导、细胞周期控制、基因方面拥有丰富经验的研究团队的专业知识 乳腺癌的监管和临床方面。在目标1中，我们将检验这样一个假设，即下调 选定的“驱动因素”lncRNA将显著影响TNBC细胞的增殖、细胞周期进程、存活、 利用该疾病的体外模型研究肿瘤细胞的迁移和侵袭。在目标2中，我们建议将 最有希望使用动物模型的lncRNA，以努力了解它们是如何启动和维持 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.