Small RNAs in Breast Cancer Metastasis

小RNA在乳腺癌转移中的作用

• 批准号: 10216199
• 负责人: Xiaoting Zhang
• 金额: $ 36.71万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216199
• 关键词: Antiestrogen Therapy; Basic Science; Bioinformatics; Biological; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer therapy; Breast cancer metastasis; Cause of Death; ChIP-seq; Clinical; Complex; Diagnostic; Disease; Distant; Endocrine; Enhancers; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor positive; Frequencies; Gene Expression; Growth; Human; Hyperactivity; In Vitro; Knowledge; Luciferases; Mediator of activation protein; Messenger RNA; Metastatic breast cancer; MicroRNAs; Mission; Molecular; Molecular Biology; Mutation; Nano delivery; Nanotechnology; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Outcome; Pathway interactions; Patients; Play; Prevention Research; Primary Neoplasm; Process; Prognostic Marker; Public Health; Publishing; RNA; Regulation; Reporter; Reporting; Research; Resistance; Role; Sampling; Site; Small RNA; Stains; System; Tamoxifen; Testing; Tissues; Translational Research; United States National Institutes of Health; Up-Regulation; Validation; Woman; Xenograft procedure; breast cancer survival; cancer therapy; cancer type; chromatin immunoprecipitation; clinically relevant; clinically significant; experimental study; genome-wide; hormone therapy; human disease; in vivo; individualized medicine; innovation; knock-down; knowledge base; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; therapeutic target; therapy resistant; transcriptome sequencing; tumor

Breast cancer is the most common type of cancer and a leading cause of death among Western women. Metastasis, a process in which primary tumor cells spread to distant sites of the body to form secondary tumors, is the primary cause of death for breast cancer patients. Most breast cancers (75%) express the estrogen receptor (ER), and both experimental and clinical evidences support key roles for ER in breast cancer metastasis. ERα antagonists such as tamoxifen have been used in ERα-positive breast cancer patients (~70% of all patients) for breast cancer prevention and treatment. Unfortunately, up to half of all ER-positive tumors either do not respond to these endocrine therapies or, after initial successful treatment, the tumors recur as endocrine-resistant breast cancer. Further, tamoxifen resistant breast cancer is known to become more aggressive and metastasize to other organs. Our recently studies supported ER coactivator MED1 as a key mediator in both tamoxifen-resistance and metastasis of human breast cancer. Importantly, MED1 overexpresses in about 40-60% of human breast cancers and the overexpression of MED1 highly correlates with poor survival of breast cancer patients. Interestingly, a recent study discovered an increased frequency of a MED1 mutation in circulating tumor cells in breast cancer patients following treatments. However, the regulation and molecular mechanisms underlying MED1 overexpression and mutation in these processes still remain poorly defined. Through both bioinformatic analyses and experimental validation, we have provided strong preliminary studies supporting that miR-205 plays an important role in regulating both MED1 expression and activation in breast cancer metastasis and resistance. Furthermore, we found that this clinically relevant MED1 mutation is hyperactive in promoting breast cancer cell metastasis and treatment resistance, as well as the expression of another class of newly identified small RNA called enhancer RNAs. Here, we will elucidate the role and molecular mechanism underlying MED1 regulation and functions in these processes using a combination of in vitro molecular biological studies, in vivo orthotopic and PDX mouse models, immuno- staining of human patient samples and RNA nanotechnology. We have assembled a strong basic and translational research team with relevant expertise to pursue the following specific aims: 1): Determine the role of the miR-205/ErbB3/ MED1 axis in tamoxifen resistance of human breast cancer; 2): Investigate the mechanisms of MED1 regulation of enhancer RNAs in breast cancer metastasis; 3): Determine the efficacy of targeting small RNAs on breast cancer therapy resistance and metastasis. Completion of this study will likely to fill a key knowledge gap in understanding novel small RNA regulatory circuits in regulating breast cancer therapy resistance and metastasis, and to make an important positive impact in providing potential novel targets for their treatment.

乳腺癌是最常见的癌症类型，也是西方女性的主要死亡原因。 转移：指原发肿瘤细胞扩散到身体远处形成继发肿瘤的过程。 肿瘤是导致乳腺癌患者死亡的主要原因。大多数乳腺癌(75%)表达 雌激素受体(ER)，以及实验和临床证据都支持ER在乳腺癌中的关键作用 转移。ERα拮抗剂，如他莫昔芬，已用于ERα阳性乳腺癌患者(~70% 在所有患者中)用于预防和治疗乳腺癌。不幸的是，多达一半的ER阳性肿瘤 要么对这些内分泌治疗没有反应，要么在最初的成功治疗后，肿瘤复发为 内分泌抵抗型乳腺癌。此外，已知对他莫昔芬耐药的乳腺癌变得更多 侵袭性和转移到其他器官。我们最近的研究支持ER辅活化子MED1是一个关键 乳腺癌三苯氧胺耐药和转移的介体。重要的是，MED1 在大约40%-60%的人类乳腺癌中过度表达，MED1的过度表达与 乳腺癌患者存活率低。有趣的是，最近的一项研究发现， 乳腺癌患者治疗后循环肿瘤细胞中的MED1突变。然而， 在这些过程中MED1过表达和突变的调控和分子机制仍然存在 仍然没有明确的定义。通过生物信息学分析和实验验证，我们提供了 强有力的初步研究支持miR-205在调节MED1表达方面发挥重要作用 和活化在乳腺癌转移和耐药中的作用。此外，我们发现这与临床相关 MED1突变在促进乳腺癌细胞转移和治疗耐药方面过度活跃 另一类新发现的称为增强子RNA的小RNA的表达。在这里，我们将澄清 MED1调控的作用和分子机制及其在这些过程中的作用 结合体外分子生物学研究，体内原位和PDX小鼠模型，免疫- 人类患者样本的染色和RNA纳米技术。我们已经集结了强大的基础和 具有相关专业知识的翻译研究团队追求以下具体目标：1)：确定角色 研究miR-205/ErbB3/MED1轴在乳腺癌三苯氧胺耐药中的作用 MED_1对乳腺癌转移中增强子RNA的调控机制3)：确定MED_1的疗效 靶向小RNA对乳腺癌治疗耐药和转移的影响。这项研究的完成很可能会 填补在理解乳腺癌调控中新的小RNA调控电路方面的关键知识空白 治疗耐药和转移，并在提供潜在的新的积极影响 他们的治疗目标。