Regulation of miRNA in breast cancer

乳腺癌中 miRNA 的调控

基本信息

批准号：
8207280
负责人：
Carolyn M. Klinge
金额：
$ 29.76万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207280
关键词：
3&apos Flanking Region 3&apos Untranslated Regions 4-Hydroxy-Tamoxifen Affect Aromatase Inhibitors BCL2 gene Binding Bioinformatics Biological Assay Biological Markers Blood Vessels Breast Breast Cancer Cell Cancer Patient Cancer cell line Cells Clinical Clinical Markers Cloning Computer Simulation Data Development Diagnostic Diagnostic Neoplasm Staging Down-Regulation Endocrine Estradiol Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor alpha Estrogen Receptors Estrogen receptor negative Estrogen receptor positive Estrogens Exploratory/Developmental Grant Functional RNA Gene Expression Gene Targeting Genes Goals Human Human Genome ICI 182780 In Vitro Individual Lead Luciferases MAPK3 gene MCF7 cell Malignant Neoplasms Mammary Neoplasms Measures Messenger RNA MicroRNAs Monitor PTEN gene Patients Pattern Positive Lymph Node Prevention Progesterone Receptors Proteins RNA Regulation Renilla Luciferases Reporter Reporting Repression Research Resistance Response Elements Reverse Transcriptase Polymerase Chain Reaction Role Sampling Seeds Selective Estrogen Receptor Modulators Site Small Interfering RNA T47D Tamoxifen Testing Therapeutic Time Transcript Transcription Factor AP-1 Transfection Translation Process Translations Tumor stage United States National Institutes of Health Western Blotting cancer therapy expression vector follow-up hormone therapy human disease in vivo inhibitor/antagonist insight mRNA Stability malignant breast neoplasm migration non-genomic novel outcome forecast overexpression promoter public health relevance research study response treatment planning tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However, ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM resistance is unknown and biomarkers of TAM-response may be useful to monitor clinical response. MicroRNAs (miRNAs) are a class of naturally-occurring, small, non-coding RNA molecules that are involved in regulating the translation and processing of mRNAs, usually by binding to the 3' untranslated region of target mRNAs and targeting the mRNA transcript to be degraded or by blocking translation. The human genome contains > 700 miRNAs. Aberrant patterns of miRNA expression have been recently implicated in human disease with miRNAs differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ER1 and progesterone receptor, tumor stage, number of positive lymph nodes, and vascular invasion. Using the NIH-R21 mechanism, we obtained preliminary data identifying miRNAs regulated by estradiol (E2) in an ER1-dependent manner in MCF-7 human breast cancer cells and identified downstream target genes that were upregulated via E2 downregulation of miR-21. However, to date, no one has examined TAM affects the pattern of miRNA expression in human breast cancer and only 2 reports have identified miRNA expression patterns in TAM-resistant derivatives of MCF-7 breast cancer cells. Specific Aim 1 is to identify miRNAs that are differentially regulated by E2 and 4-hydroxyTAM (4-OHT) in antiestrogen- sensitive MCF-7 and T47D breast cancer cells. Specific Aim 2 is to identify miRNAs and their target genes in antiestrogen/ TAM- sensitive versus -resistant breast cancer cell lines and tumor xenografts. This Aim tests the hypothesis that miRNA expression is dysregulated in endocrine/TAM- resistant versus -sensitive breast cancer cells. Specific Aim 3 is to determine if the E2- regulated and 4-OHT- regulated miRNAs identified in breast cancer cell lines show aberrant expression in human breast tumors and correlate with clinical diagnostic measures and patient response to tamoxifen therapy. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic. PUBLIC HEALTH RELEVANCE: Aromatase inhibitor therapy is not useful for all ER1 positive breast cancer patients and the selective estrogen receptor modulator tamoxifen (TAM) remains the most widely used endocrine therapy for the treatment and prevention of estrogen receptor alpha (ER1) positive breast cancer. However, ~ 40% of initially TAM-sensitive tumors become endocrine/TAM-resistant. The mechanism behind such acquired TAM/endocrine resistance is unknown. The overall goal of the proposed research is to determine the identity and gene targets of miRNAs that may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain endocrine/TAM-resistance and become invasive and metastatic.

描述（由申请人提供）：选择性雌激素受体调节剂（SERM）他莫昔芬（TAM）是用于治疗和预防雌激素受体α（ER1）阳性乳腺癌的最广泛使用的内分泌疗法。但是，约有40％的最初对TAM敏感的肿瘤成为内分泌/TAM耐药性。这种获得的TAM耐药性背后的机制尚不清楚，TAM反应的生物标志物可能对监测临床反应有用。 microRNA（miRNA）是一类天然的，小的，非编码的RNA分子，与调节mRNA的翻译和处理有关，通常是通过与靶mRNA的3'未翻译区域结合并靶向mRNA转录本的3'未翻译区域，以脱落或通过阻止翻译来进行脱位。人基因组包含> 700个miRNA。最近，miRNA表达的异常模式与人类疾病有关，miRNA与其他公认的乳腺癌阶段和患者预后相一致的标记差异表达，包括ER1和孕酮受体，肿瘤阶段，阳性淋巴结的数量和血管入侵。使用NIH-R21机制，我们获得了以ER1依赖性方式在MCF-7人类乳腺癌细胞中以ER1依赖性方式鉴定的miRNA的初步数据，并通过E2下调miR-21鉴定了下游靶基因。然而，迄今为止，没有人检查TAM会影响人类乳腺癌中miRNA的表达模式，只有2个报告鉴定了MCF-7乳腺癌细胞的TAM抗性衍生物中的miRNA表达模式。具体目的1是鉴定在抗雌激素敏感的MCF-7和T47D乳腺癌细胞中由E2和4-羟基坦（4-OHT）差异调节的miRNA。具体目标2是在抗雌激素/ TAM敏感的乳腺癌细胞系和肿瘤异种移植物中鉴定miRNA及其靶基因。这个目的检验了以下假设：在内分泌/抗敏感性乳腺癌细胞中，miRNA表达失调。具体目的3是确定在乳腺癌细胞系中鉴定出的E2调控和4-OHT调节的miRNA是否在人乳腺肿瘤中表现异常，并与临床诊断措施以及患者对他莫昔芬治疗的反应相关。拟议研究的总体目标是确定miRNA的身份和基因靶标，这些靶标可能会为乳腺肿瘤获得内分泌/TAM抗性并成为侵入性和转移性的机制提供新颖的生物标志物和新见解。公共卫生相关性：芳香酶抑制剂疗法对所有ER1乳腺癌患者均不有用，选择性雌激素受体调节蛋白莫昔芬（TAM）仍然是最广泛使用的内分泌治疗，用于治疗和预防雌激素受体α（ER1）阳性乳腺癌。但是，约有40％的最初对TAM敏感的肿瘤成为内分泌/TAM耐药性。这种获得的TAM/内分泌耐药性背后的机制尚不清楚。拟议研究的总体目标是确定miRNA的身份和基因靶标，这些靶标可能会为乳腺肿瘤获得内分泌/TAM抗性并成为侵入性和转移性的机制提供新颖的生物标志物和新见解。