miR-140 and Breast Cancer Prevention

描述（由申请人提供）：导管原位癌（DCIS）患者即使在接受乳房手术后也有发生复发或浸润性乳腺癌的显著风险。因此，女性可以从降低DCIS复发率的化学预防策略中受益。然而，DCIS发展的分子机制仍不清楚，因此确定可以预防的靶向途径非常重要。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，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细胞中miR-140的表达。我们进一步观察到，miR-140表达减少与SIRT 1组蛋白脱乙酰酶表达增加相关，SIRT 1组蛋白脱乙酰酶与癌症干细胞存活率增加相关。最后，miR-140敲除小鼠在11个月大时自发发生DCIS。我们的初步数据表明，miR-140和SIRT 1在DCIS的发展中发挥作用。基于这些结果，我们假设miR-140缺失导致SIRT 1表达增加，从而驱动DCIS发展和乳腺癌干细胞积累增加。我们进一步提出萝卜硫素治疗可以恢复miR-140水平，然后靶向并抑制SIRT 1水平以防止DCIS发展。具体目标1将定义miR-140在DCIS转化中失活的机制。具体目标2旨在确定miR-140对DCIS转化中癌症干细胞存活的影响。具体目标3旨在表征miR-140在体内莱菔硫烷化学预防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发展的新机制和萝卜硫素依赖性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细胞和动物模型。

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.