Small RNAs in Breast Cancer Metastasis

小RNA在乳腺癌转移中的作用

• 批准号: 10020911
• 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/10020911
• 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.

乳腺癌是最常见的癌症类型，也是西方女性死亡的主要原因。 转移，原发性肿瘤细胞扩散到身体远处部位形成继发性肿瘤的过程 肿瘤，是乳腺癌患者死亡的首要原因。大多数乳腺癌（75%）表达 雌激素受体 (ER)，实验和临床证据均支持 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（约 70%） 所有患者）用于乳腺癌的预防和治疗。不幸的是，多达一半的 ER 阳性肿瘤 要么对这些内分泌疗法没有反应，要么在最初成功的治疗后，肿瘤复发 内分泌抵抗性乳腺癌。此外，已知对他莫昔芬耐药的乳腺癌变得更加严重。 具有侵袭性并转移至其他器官。我们最近的研究支持 ER 辅激活因子 MED1 作为关键 人类乳腺癌他莫昔芬耐药性和转移的介质。重要的是，MED1 在大约 40-60% 的人类乳腺癌中过度表达，并且 MED1 的过度表达高度相关 乳腺癌患者的生存率很低。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出现 MED1 突变。然而， 这些过程中 MED1 过表达和突变的调控和分子机制仍然存在 仍然不明确。通过生物信息分析和实验验证，我们提供了 强有力的初步研究支持 miR-205 在调节 MED1 表达中发挥重要作用 以及乳腺癌转移和抵抗力的激活。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性方面异常活跃，以及 另一类新发现的小RNA（称为增强子RNA）的表达。在这里，我们将阐明 MED1 调控的作用和分子机制以及这些过程中的功能 结合体外分子生物学研究、体内原位和 PDX 小鼠模型、免疫 人类患者样本染色和 RNA 纳米技术。我们已经组建了强大的基础和 具有相关专业知识的转化研究团队，以实现以下具体目标： 1)：确定角色 miR-205/ErbB3/MED1 轴在人乳腺癌他莫昔芬耐药中的作用； 2）：调查 MED1对乳腺癌转移中增强子RNA的调控机制； 3): 确定功效 靶向小RNA对乳腺癌治疗耐药性和转移的影响。完成这项研究可能会 填补了解调节乳腺癌的新型小RNA调节回路的关键知识空白 治疗耐药和转移，并在提供潜在的新药方面产生重要的积极影响 他们的治疗目标。