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着风险。因此，女性将受益于降低导管原位癌复发率的化学预防策略。然而，DCIS 发展的分子机制仍不清楚，因此确定可作为预防目标的途径非常重要。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（十字花科蔬菜的一种关键生物活性成分）可以恢复原代 DCIS 细胞中的 miR-140 表达。我们进一步观察到，miR-140 表达减少与 SIRT1 组蛋白脱乙酰酶表达增加相关，而 SIRT1 组蛋白脱乙酰酶与癌症干细胞存活率增强相关。最后，miR-140 基因敲除小鼠在 11 个月大时自发患上导管原位癌 (DCIS)。我们的初步数据表明 miR-140 和 SIRT1 在 DCIS 发展中发挥作用。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 发展并增加乳腺癌干细胞的积累。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 SIRT1 水平以预防 DCIS 发展。具体目标 1 将定义 DCIS 转化中 miR-140 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 在萝卜硫素体内化学预防 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模型和动物模型。

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.