miR-140 and Breast Cancer Prevention

miR-140 与乳腺癌预防

• 批准号: 8633435
• 负责人: Qun Zhou
• 金额: $ 30.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633435
• 关键词: 3' Untranslated Regions; Accounting; Age-Months; Animal Model; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Prevention; Breast Carcinoma; Breast Epithelial Cells; Breast-Conserving Surgery; Broccoli - dietary; Cell Culture Techniques; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; DNA Methylation; DNA Modification Process; Data; Development; Diet; Epigenetic Process; Frequencies; Genes; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Incidence; Knock-out; Knockout Mice; Lead; Malignant - descriptor; Mammary Neoplasms; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Noninfiltrating Intraductal Carcinoma; Pathway interactions; Patients; Prevention; Proteins; Radiation therapy; Recurrence; Regulation; Repression; Risk; Role; Route; Sampling; Staging; Stem cells; Sulforaphane; System; Testing; Tissues; Translations; Woman; Xenograft Model; base; breast surgery; cancer stem cell; cell transformation; chromatin modification; cruciferous vegetable; design; high risk; in vitro Model; in vivo; innovation; malignant breast neoplasm; neoplastic; neoplastic cell; overexpression; prevent; promoter; research study; response; self-renewal; stem cell population; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Patients with ductal carcinoma in situ (DCIS) have significant risks of developing recurrence or invasive breast cancer even after they receive breast surgery. Thus, women stand to benefit from chemoprevention strategies that reduce the incidence of DCIS recurrence. However, the molecular mechanisms that underlie DCIS development remain unclear and so it is important to identify pathways that could be targeted for prevention. Our preliminary studies showed that loss of microRNA-140 (miR-140) expression is associated with the development of DCIS and that sulforaphane (a key bioactive ingredient of cruciferous vegetables) can restore miR-140 expression in primary DCIS cells. We further observed that reduced miR-140 expression is associated with increased expression of the SIRT1 histone deacetylase that is associated with enhanced cancer stem cell survival. Finally, miR-140 knockout mice spontaneously developed DCIS at 11 months of age. Our preliminary data suggest that miR-140 and SIRT1 have roles in DCIS development. Based on these results, we hypothesize that miR-140 loss leads to increased SIRT1 expression which drives DCIS development and increased accumulation of breast cancer stem cells. We further propose that sulforaphane treatment can restore miR-140 level which then targets and suppresses SIRT1 level to prevent DCIS development. Specific Aim 1 will define the mechanism of miR-140 inactivation in DCIS transformation. Specific Aim 2 is designed to determine the impact of miR-140 on cancer stem cell survival in DCIS transformation. Specific Aim 3 is designed to characterize the role of miR-140 in sulforaphane chemoprevention of DCIS in vivo. We believe that these studies are innovative and "high impact" because findings from our studies will identify a new mechanism of DCIS development and a new route of sulforaphane-dependent breast cancer prevention. We have developed all of the cell-based and animal models necessary to complete these studies.

描述(申请人提供)：导管原位癌(DCIS)患者即使在接受乳房手术后仍有发生复发或浸润性乳腺癌的巨大风险。因此，妇女将受益于减少DCIS复发的化学预防策略。然而，DCIS发生的分子机制尚不清楚，因此确定可以作为预防目标的途径是重要的。我们的初步研究表明，microRNA-140(miR-140)的表达缺失与DCIS的发生发展有关，萝卜硫素(十字花科蔬菜的关键生物活性成分)可以恢复原代DCIS细胞miR-140的表达。我们进一步观察到，miR-140表达减少与SIRT1组蛋白去乙酰化酶表达增加有关，这与提高癌症干细胞存活率有关。最后，miR-140基因敲除小鼠在11个月大时自发发展为DCIS。我们的初步数据表明miR-140和SIRT1在DCIS的发生发展中起作用。基于这些结果，我们假设miR-140缺失导致SIRT1表达增加，从而驱动DCIS的发展和乳腺癌干细胞的增加积累。我们进一步提出萝卜硫素治疗可以恢复miR-140的水平，从而靶向和抑制SIRT1的水平，从而阻止DCIS的发展。具体目标1将确定DCIS转化过程中miR-140失活的机制。具体目的2旨在确定miR-140在DCIS转化过程中对肿瘤干细胞存活的影响。具体目的3旨在研究miR-140在体内萝卜硫素化学预防DCIS中的作用。我们相信，这些研究具有创新性和“高影响力”，因为我们的研究结果将确定DCIS发展的新机制和依赖萝卜硫素的乳腺癌预防的新途径。我们已经开发了完成这些研究所需的所有基于细胞的模型和动物模型。