Small RNAs in Breast Cancer Metastasis

小RNA在乳腺癌转移中的作用

• 批准号: 9817096
• 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/9817096
• 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; Hyperactive behavior; 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.

乳腺癌是西方妇女中最常见的癌症类型，也是主要的死亡原因。 转移，一个过程，原发性肿瘤细胞扩散到人体的远处形成次级 肿瘤是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（例如他莫昔芬）已用于ERα阳性乳腺癌患者（约70％） 在所有患者中）预防乳腺癌和治疗。不幸的是，所有ER阳性肿瘤的最多一半 要么不对这些内分泌疗法反应 内分泌乳腺癌。此外，已知他莫昔芬抗乳腺癌会变得更多 侵略性和转移到其他器官。我们最近的研究支持ER共激活器Med1作为关键 他莫昔芬抗性和人类乳腺癌转移的介体。重要的是，Med1 大约40-60％的人乳腺癌过表达，而Med1的过表达高度相关 乳腺癌患者的存活不良。有趣的是，最近的一项研究发现 治疗后，乳腺癌患者循环肿瘤细胞中的MED1突变。但是， 在这些过程中，MED1过表达和突变的调节和分子机制仍然 保持较差。通过生物信息学分析和实验验证，我们提供了 强大的初步研究支持miR-205在调节这两种Med1表达中起重要作用 和乳腺癌转移和抗药性的激活。此外，我们发现该临床相关 Med1突变在促进乳腺癌细胞转移和治疗耐药性方面过度活跃，以及 另一类新鉴定的小RNA的表达称为增强子RNA。在这里，我们将阐明 Med1调节的作用和分子机制在这些过程中使用A 体外分子生物学研究的结合，体内原位和PDX小鼠模型，免疫 - 人类患者样品和RNA纳米技术的染色。我们已经组装了一个强大的基础和 具有相关专家的转化研究团队以追求以下特定目的：1）：确定角色 他莫昔芬对人类乳腺癌的耐药性中的miR-205/ erbb3/ med1轴； 2）：调查 Med1调节增强子RNA在乳腺癌转移中的机制； 3）：确定效率 针对乳腺癌疗法耐药性和转移的小RNA。这项研究的完成可能会 填补关键知识差距，以了解控制乳腺癌的新型小RNA调节电路 治疗耐药性和转移，并在提供潜在的新颖性方面产生重要的积极影响 他们的治疗目标。