Regulation of miRNA expression in breast cancer cells

乳腺癌细胞中 miRNA 表达的调控

• 批准号: 7428783
• 负责人: Carolyn M. Klinge
• 金额: $ 14.77万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7428783
• 关键词: 3' 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; Class; 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; Invasive; Lead; MCF7 cell; Mammary Neoplasms; Measures; Mediating; Messenger RNA; Methods; MicroRNAs; Monitor; Numbers; Patients; Pattern; Phenotype; Positive Lymph Node; Prevention; Progesterone; 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; Tamoxifen; Testing; Therapeutic; Thinking; 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

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（ERα）阳性乳腺癌的最广泛使用的内分泌疗法。然而，通过辅助治疗，最初对 TAM 敏感的肿瘤会变得对 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，与小干扰 RNA (siRNA) 相关但又不同。 miRNA 参与调节 mRNA 的翻译和加工，通常通过与目标 mRNA 的 3' 非翻译区结合并靶向要降解的 mRNA 转录本。人类基因组被认为含有超过 400 个 miRNA。最近，人类乳腺癌涉及 miRNA 表达的异常模式，一项研究表明 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一致，包括 ERα 和孕激素受体表达、肿瘤分期、阳性数量淋巴结、血管侵犯。然而，迄今为止，尚未有人研究雌二醇 (E2) 或选择性 ER 调节剂/抗雌激素是否影响人类乳腺癌中 miRNA 的表达模式，或者 miRNA 的表达模式是否与获得性抗雌激素耐药相关。具体目标 1 是鉴定抗雌激素敏感的 MCF-7 乳腺癌细胞中受雌二醇 (E2) 和 4-羟基他莫昔芬 (4-OHT) 调节的 miRNA。目标 1 检验 E2 和 4-OHT 差异调节人乳腺癌细胞中 miRNA 表达的假设。此外，我们认为这些 miRNA 反过来调节编码参与分化和细胞增殖的蛋白质的基因的 mRNA 稳定性。具体目标 2 测试了以下假设：抗雌激素/TAM 耐药性与敏感性乳腺癌细胞中 miRNA 表达失调。具体目标 3 是确定在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，并与患者对他莫昔芬治疗的反应相关。我们的长期希望是，miRNA 可以为乳腺肿瘤获得 TAM/抗雌激素耐药性并变得侵袭性和转移性的机制提供新的生物标志物和新的见解。