miR-140 and Breast Cancer Prevention

miR-140 与乳腺癌预防

• 批准号: 8490524
• 负责人: Qun Zhou
• 金额: $ 29.94万
• 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/8490524
• 关键词: 3' Untranslated Regions; Accounting; Age-Months; Animal Model; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Prevention; Breast Carcinoma; Breast-Conserving Surgery; Broccoli - dietary; Cell Culture Techniques; Cell Survival; Cells; Chemoprevention; Chemopreventive Agent; DNA Methylation; DNA Modification Process; Data; Development; Diet; Epigenetic Process; Epithelial Cells; Frequencies; Genes; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Incidence; Knock-out; Knockout Mice; Lead; Malignant - descriptor; Mammary Neoplasms; Mammary gland; 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（由申请人提供）：即使接受乳房手术后，有导管癌（DCIS）的导管癌患者即使他们接受复发或侵入性乳腺癌的危险。因此，妇女将受益于减少DCIS复发率的化学预防策略。但是，DCIS发育构成的分子机制尚不清楚，因此鉴定可以针对预防的途径很重要。我们的初步研究表明，microRNA-140（miR-140）表达的丧失与DCIS的发展有关，硫烷（十字花科蔬菜的关键生物活性成分）可以恢复原代DCIS细胞中的miR-140表达。我们进一步观察到，降低的miR-140表达与SIRT1组蛋白脱乙酰基酶的表达增加有关，这与增强的癌症干细胞存活有关。最终，miR-140敲除小鼠在11个月大时自发发展了DCIS。我们的初步数据表明，miR-140和SIRT1在DCIS开发中具有作用。基于这些结果，我们假设miR-140损失会导致SIRT1表达增加，从而驱动DCIS发育并增加乳腺癌干细胞的积累。我们进一步提出，硫烷治疗可以恢复miR-140水平，然后靶向并抑制SIRT1水平以防止DCIS发育。具体目标1将定义DCIS转化中miR-140失活的机理。特定目标2旨在确定miR-140对DCIS转化中癌症干细胞存活的影响。特定的目标3旨在表征miR-140在体内DCIS硫烷化学预防中的作用。我们认为，这些研究具有创新性和“高影响力”，因为我们研究的发现将确定DCIS发育的新机制以及硫磺依赖性乳腺癌的新途径。我们已经开发了完成这些研究所需的所有基于细胞和动物的模型。