MicroRNAs to Understand Cause and Outcome in Breast Cancer

描述（由申请人提供）：MicroRNAs （miRNAs）是全球性的RNA调控因子，是细胞存活和增殖途径的重要主控因子，在癌症发展和肿瘤维持中起着至关重要的作用。我们和其他人最近的证据表明，mrna的3‘非翻译区（3’ utrs）的miRNA结合位点多态性可以强烈影响癌症风险，并且肿瘤中的miRNA表达模式是预后和治疗反应的重要生物标志物。我们假设miRNA的研究进展可以应用于乳腺癌。根据受体分子ER（雌激素）、PR（孕激素）和HER2/neu的表达，乳腺癌主要有3种亚型。所有这些受体均阴性的乳腺癌（三阴性乳腺癌[TNBC]）预后最差，对这种亚型的病因和危险因素知之甚少。我们假设miRNA生物学新领域的进展可以应用于TNBC，以识别风险和结果的新生物标志物，并了解疾病的基本机制。本提案的总体目标是研究miRNA 3'UTR多态性作为乳腺癌的启动事件，并确定miRNA表达模式的预测作用，以确定对治疗反应和结果的生物标志物。我们最终将通过体内异种移植和转基因小鼠模型验证我们的发现，即3'UTR多态性和错误调控的mirna是乳腺癌发展的关键。通过实现这些目标，我们将能够对女性患乳腺癌的风险进行适当的风险分层，并识别生物标志物，预测她们对治疗的反应和最终结果。我们希望深入了解乳腺癌发展背后的基础生物学，并进一步确定mirna作为乳腺癌反应的新靶点，从而在女性个性化医疗方面取得重大进展。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are global RNA regulators and important master controllers of the cell survival and proliferation pathways that are critically important in cancer development and tumor maintenance. Recent evidence from our group and others show that miRNA binding site polymorphisms in the 3' untranslated regions (3'UTRs) of mRNAs can strongly impact cancer risk, and that miRNA expression patterns in tumors are important biomarkers of outcome and treatment response. We hypothesize that advances in miRNA understanding can be applied to breast cancer. Breast cancer has 3 main sub-types based on expression of the receptor molecules ER (estrogen), PR (progesterone) and HER2/neu. Breast cancers negative for all of these receptors (triple negative breast cancer [TNBC]) have the worst outcome, and little is known about the etiology and risk factors for this sub-type. We hypothesize that advances in the novel area of miRNA biology can be applied to TNBC to identify novel biomarkers of risk and outcome as well as understand fundamental mechanisms of disease. The overall goal of this proposal is to study miRNA 3'UTR polymorphisms as initiating events in breast cancer, and to define the predictive role of miRNA expression patterns to identify biomarkers of response to therapy and outcome. We will ultimately test our findings that 3'UTR polymorphisms and misregulated miRNAs are key in breast cancer development using in vivo xenograft and transgenic mouse models. By accomplishing these aims we will be able to appropriately risk stratify women for the risk of developing breast cancer, as well as identify biomarkers predicting their response to therapy and ultimate outcome. We expect to gain insight into the fundamental biology behind breast cancer development, and to further identify miRNAs that are new targets in breast cancer response, to make significant strides towards personalized medicine for women.