Regulation of miRNA in breast cancer

乳腺癌中 miRNA 的调控

• 批准号: 7779660
• 负责人: Carolyn M. Klinge
• 金额: $ 30.55万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 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/7779660
• 关键词: 3' Flanking Region; 3' 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; Estrogens; Exploratory/Developmental Grant; Functional RNA; Gene Expression; Gene Targeting; Genes; Goals; Human; Human Genome; ICI 182780; In Vitro; Individual; Lead; Luciferases; 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; Transfection; Translation Process; Translations; Tumor stage; Untranslated Regions; 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

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。然而，约 40% 最初对 TAM 敏感的肿瘤会变得内分泌/TAM 耐药。这种获得性 TAM 耐药性背后的机制尚不清楚，TAM 反应的生物标志物可能有助于监测临床反应。 MicroRNA (miRNA) 是一类天然存在的小非编码 RNA 分子，参与调节 mRNA 的翻译和加工，通常通过与目标 mRNA 的 3' 非翻译区结合并将 mRNA 转录物靶向降级或阻止翻译。人类基因组包含超过 700 个 miRNA。最近，miRNA 表达的异常模式与人类疾病有关，miRNA 的差异表达与其他已确定的乳腺癌分期和患者预后标志物（包括 ER1 和孕激素受体、肿瘤分期、阳性淋巴结数量和血管侵犯）一致。利用 NIH-R21 机制，我们获得了初步数据，鉴定了 MCF-7 人乳腺癌细胞中雌二醇 (E2) 以 ER1 依赖性方式调节的 miRNA，并鉴定了通过 E2 下调 miR-21 上调的下游靶基因。然而，迄今为止，还没有人研究过 TAM 对人类乳腺癌中 miRNA 表达模式的影响，并且只有 2 份报告鉴定了 MCF-7 乳腺癌细胞的 TAM 抗性衍生物中的 miRNA 表达模式。具体目标 1 是鉴定抗雌激素敏感性 MCF-7 和 T47D 乳腺癌细胞中受 E2 和 4-羟基TAM (4-OHT) 差异调节的 miRNA。具体目标 2 是鉴定抗雌激素/TAM 敏感与耐药乳腺癌细胞系和肿瘤异种移植物中的 miRNA 及其靶基因。该目的测试了内分泌/TAM 耐药性与敏感性乳腺癌细胞中 miRNA 表达失调的假设。具体目标 3 是确定乳腺癌细胞系中鉴定的 E2 调节和 4-OHT 调节 miRNA 是否在人类乳腺肿瘤中表现出异常表达，并与临床诊断措施和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 miRNA 可能会提供新的生物标志物，并为乳腺肿瘤获得内分泌/TAM 耐药性并变得侵袭性和转移性的机制提供新的见解。 公共健康相关性：芳香酶抑制剂疗法并不适用于所有 ER1 阳性乳腺癌患者，选择性雌激素受体调节剂他莫昔芬 (TAM) 仍然是治疗和预防雌激素受体 α (ER1) 阳性乳腺癌最广泛使用的内分泌疗法。然而，约 40% 最初对 TAM 敏感的肿瘤会变得内分泌/TAM 耐药。这种获得性 TAM/内分泌抵抗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 miRNA 可能会提供新的生物标志物，并为乳腺肿瘤获得内分泌/TAM 耐药性并变得侵袭性和转移性的机制提供新的见解。