Role of EZH2 in Breast Cancer Progression

描述(申请人提供)：虽然一般来说，原发肿瘤越大，其转移或已经转移的可能性就越大，但情况并不总是如此。许多小乳腺癌会发生转移，结果令人沮丧。表征驱动这些肿瘤快速发展的基因可能会识别新的生物标记物，以帮助临床医生指导当前的治疗，并可能提供新的治疗靶点。我们发现EZH2在55%的浸润性乳腺癌中高表达，是预后不良的独立组织生物标志物。EZH2是一种多梳状蛋白，负责在连续几代细胞中保持细胞的特性。在之前的资金周期中，我们已经证明了EZH2蛋白在从正常乳腺到导管原位癌(浸润性癌的先兆)到浸润性癌(转移性最高)的发展过程中上调。EZH2在体内和体外触发侵袭并调节乳腺癌的生长。我们的实验室提供了EZH2和BRCA1之间的第一个机制联系。EZH2控制BRCA1在乳腺细胞上的细胞内分布，并以BRCA1依赖的方式调节G2和有丝分裂之间的过渡以及细胞的增殖。我们实验室的一项主要成就是建立了乳腺特异的EZH2转基因小鼠模型。EZH2转基因小鼠发生上皮管内增生，核BRCA1蛋白下调，组织学特征重现人类疾病。基于这项工作，我们竞争更新的中心假设是，EZH2在乳腺中的过度表达通过调节BRCA1蛋白和功能而诱导增生。我们进一步假设，在EZH2过度表达的背景下，额外的特定致癌事件会触发从一开始就具有高度侵袭性的癌症的快速发展。本研究的具体目的是：1.研究EZH2在转基因小鼠乳腺中的过度表达是否加速肿瘤的发生和转移；目的2.确定EZH2调节BRCA1蛋白和BRCA1介导的抑癌功能的机制；目的3.评价单独检测EZH2或联合检测BRCA1的临床应用价值：(A)作为乳腺癌风险增加的组织生物标志物，以及(B)作为能够识别哪些小的浸润性癌具有高转移潜能的生物标志物。我们将使用独特的资源来研究人类中EZH2过度表达对BRCA1的影响，这些资源包括后来发展为乳腺癌的女性的良性乳腺组织，以及一组只有1期和2期(&lt；2厘米)的乳腺浸润性癌，并进行了10年的随访。这些研究将提供更好的诊断、更准确的预后不良预测以及开发新疗法的潜力。 公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。这项研究涉及女性健康的一个重要方面；即EZH2如何调节乳腺上皮细胞的增殖和分化，以促进早期导管内增生，重述人类疾病。我们将研究EZH2如何与其他特定的致癌事件合作，触发侵袭性癌症的发展，这些癌症从一开始就具有高度的侵袭性，而且尽管诊断时体积很小，但仍然可以转移。如果我们能防止或抑制EZH2在乳腺上皮和肿瘤中的过度表达，我们将极大地改善乳腺癌的预后，拯救数百万妇女的生命。这些研究可能形成乳腺癌干预和治疗的基础，潜在地防止癌前病变变得恶性和转移。

DESCRIPTION (provided by applicant): Although in general, the larger the primary tumor the greater the likelihood that it will metastasize or already has metastasized, this is not always the case. Many small breast cancers develop metastasis and have a discouraging outcome. Characterizing genes that drive these tumors' rapid progression may identify novel biomarkers to help clinicians guide current treatments, and may offer novel therapeutic targets. We have discovered that EZH2 is over expressed in 55% of invasive breast carcinomas and is an independent tissue biomarker of poor outcome. EZH2 is a Polycomb group protein responsible for maintaining cell identity through successive generations of cells. During the previous funding cycle, we have demonstrated that EZH2 protein is up regulated during progression from normal breast to ductal carcinoma in situ, the precursor of invasive carcinoma, to invasive carcinoma, being highest at the metastasis. EZH2 triggers invasion and regulates breast cancer growth in vivo and in vitro. Our lab has provided the first mechanistic link between EZH2 and BRCA1. EZH2 controls the intracellular distribution of BRCA1 on breast cells and regulates the transition between G2 and mitosis and cell proliferation in a BRCA1-dependent manner. A major accomplishment of our laboratory has been the development of a mammary specific EZH2 transgenic mouse model. EZH2 transgenic mice develop epithelial intraductal hyperplasia with down regulation of nuclear BRCA1 protein and histological features recapitulating human disease. Based on this body of work, the central hypothesis of our competing renewal is that EZH2 over expression in the mammary gland induces hyperplasia by regulating BRCA1 protein and function. We further hypothesize that additional specific oncogenic events in the setting of EZH2 overexpression, trigger the rapid development of carcinomas that are highly aggressive from the outset. The specific aims are: Aim 1. To investigate if EZH2 over expression in the mammary gland of transgenic mice accelerates tumor development and metastasis using well-characterized models of breast tumor genesis that recapitulate EZH2 over expressing human invasive breast carcinomas; Aim 2. To determine the mechanism by which EZH2 regulates BRCA1 protein and BRCA1-mediated tumor suppressor functions; Aim 3. To evaluate the clinical usefulness of detecting EZH2 alone or in combination with BRCA1 (a) as a tissue biomarker of increased breast cancer risk, and (b) as a biomarker able to identify which small invasive carcinomas have high metastatic potential. We will investigate the effect of EZH2 over expression on BRCA1 in humans using unique resources consisting of benign breast tissues of women who subsequently developed breast cancer, and a cohort of invasive carcinomas of the breast exclusively of Stages 1 and 2 (< 2 cm) with 10 years of follow-up. These studies will provide better diagnosis, more accurate predicting of poor prognosis and the potential to develop new therapies. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health; that of how EZH2 regulates the proliferation and differentiation of breast epithelial cells to promote early intraductal hyperplasia recapitulating human disease. We will study how EZH2 cooperates with other specific oncogenic events to trigger the development of invasive carcinomas that are highly aggressive from the outset, and that can metastasize despite their small size at diagnosis. If we could prevent or inhibit EZH2 over expression in the mammary epithelium and in tumors, we would greatly improve breast cancer outcome and save the lives of millions of women. These studies may form the basis of intervention and therapy in breast cancer, potentially preventing premalignant lesions from becoming malignant and metastasizing.