Regulation of miRNA expression in breast cancer cells

乳腺癌细胞中 miRNA 表达的调控

基本信息

批准号：
7846933
负责人：
Carolyn M. Klinge
金额：
$ 1.66万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846933
关键词：
3&apos Untranslated Regions 4-Hydroxy-Tamoxifen Adjuvant Therapy Affect Binding Binding Sites Biological Assay Biological Markers Blood Vessels Breast Cancer Cell Cancer cell line Cell Line Cell Proliferation Cells Cessation of life Clinical Cloning Development Diagnostic Diagnostic Neoplasm Staging Estradiol Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptor alpha Estrogens Functional RNA Gene Targeting Genes Goals Human Human Genome ICI 182780 Individual Lead MCF7 cell Mammary Neoplasms Measures Mediating Messenger RNA Methods MicroRNAs Monitor Patients Pattern Phenotype Positive Lymph Node Prevention Progesterone Receptors Proteins RNA Regulation Renilla Luciferases Reporter Reporting Research Resistance Response Elements Reverse Transcriptase Polymerase Chain Reaction Role Sampling Selective Estrogen Receptor Modulators Site Small Interfering RNA Suppressor Genes Tamoxifen Testing Therapeutic Time Transcript Transfection Translation Process Tumor Suppressor Genes Tumor stage Untranslated Regions cancer recurrence cancer therapy design gene function hormone therapy inhibitor/antagonist insight lymph nodes mRNA Stability mRNA Transcript Degradation malignant breast neoplasm novel outcome forecast promoter receptor expression research study resistance mechanism response treatment planning tumor

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 (ERalpha) positive breast cancer. With adjuvant therapy, however, initially TAM-sensitive tumors become 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 related to, but distinct from, small interfering RNAs (siRNAs). miRNAs 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. The human genome is thought to contain > 400 miRNAs. Abberant patterns of miRNA expression have been recently implicated in human breast cancer and one study showed that miRNAs were differentially expressed in concordance with other well-established markers of breast cancer stage and patient prognosis including ERalpha and progesterone receptor expression, tumor stage, number of positive lymph nodes, and vascular invasion. However, to date, no one has examined whether estradiol (E2) or selective ER modulators/antiestrogens affect the pattern of miRNA expression in human breast cancer or whether miRNA expression patterns correlate with acquired antiestrogen-resistance. Specific Aim 1 is to identify miRNAs that are regulated by estradiol (E2) and 4-hydroxytamoxifen (4-OHT) in antiestrogen-sensitive MCF-7 breast cancer cells. Aim 1 tests the hypothesis that E2 and 4-OHT differentially regulate the expression of miRNAs in human breast cancer cells. Further, we suggest these miRNAs in turn regulate the mRNA stability of genes encoding proteins involved in differentiation and cell proliferation. Specific Aim 2 tests the hypothesis that miRNA expression is dysregulated in antiestrogen/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 patient response to tamoxifen therapy. It is our long term hope that miRNAs may provide novel biomarkers and new insights into the mechanisms by which breast tumors gain TAM/antiestrogen-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（Eralpha）阳性乳腺癌的最广泛使用的内分泌疗法。然而，使用辅助治疗，最初对TAM敏感的肿瘤变得抗TAM。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，小的，非编码的RNA分子，与小型干扰RNA（siRNA）相关，但与众不同。 miRNA参与调节mRNA的翻译和加工，通常通过与靶mRNA的3'未翻译区域结合并靶向以降解的mRNA转录本。人类基因组被认为包含> 400个miRNA。最近，miRNA表达的浓烈模式与人类乳腺癌有关，一项研究表明，miRNA与其他公认的乳腺癌阶段和患者预后相一致，包括ERALPHA和孕酮受体表达，肿瘤阶段，阳性淋巴结阳性淋巴结和血管入侵。但是，迄今为止，没有人检查雌二醇（E2）或选择性ER调节剂/抗雌激素是否会影响人类乳腺癌中miRNA表达的模式，或者miRNA表达模式是否与获得的抗抗抑制相关。具体目标1是鉴定受雌激素敏感的MCF-7乳腺癌细胞中雌二醇（E2）和4-羟基莫昔芬（4-OHT）调节的miRNA。 AIM 1检验了以下假设：E2和4-OHT差异化调节人类乳腺癌细胞中miRNA的表达。此外，我们建议这些miRNA反过来调节编码涉及分化和细胞增殖的蛋白质的基因的mRNA稳定性。具体目标2检验了miRNA表达在抗雌激素/抗TAM抗敏感性乳腺癌细胞中失调的假设。具体目的3是确定在乳腺癌细胞系中鉴定出的E2调节和4-OHT调节的miRNA是否在人乳腺肿瘤中表现异常，并且与患者对他莫昔芬治疗的反应相关。我们的长期希望，miRNA可以为乳腺肿瘤获得TAM/抗雌激素耐药性并变得侵入性和转移性的机制提供新颖的生物标志物和新见解。