Role of EZH2 in Breast Cancer Progression

摘要 虽然一般来说，原发肿瘤越大，转移或转移的可能性就越大。 已经转移了，但情况并非总是如此。许多小乳腺癌发生转移， 结果令人沮丧描述驱动这些肿瘤快速发展的基因可以识别 新的生物标志物，以帮助临床医生指导目前的治疗，并可能提供新的治疗目标。我们 已经发现EZH 2在55%的浸润性乳腺癌中过表达，并且是一种独立的 组织生物标志物结果不佳。EZH 2是一种多梳组蛋白，负责维持细胞 通过连续几代细胞的身份。在上一个融资周期，我们已经证明， EZH 2蛋白在从正常乳腺到导管原位癌的进展过程中上调， 浸润性癌的前体，到浸润性癌，在转移时最高。EZH 2触发器 侵袭和调节乳腺癌生长在体内和体外。我们的实验室提供了第一个 EZH 2和BRCA 1之间的联系。EZH 2控制BRCA 1在乳腺细胞上的细胞内分布， 以BRCA 1依赖性方式调节G2和有丝分裂之间的过渡以及细胞增殖。一 我们实验室的主要成就是开发了乳腺特异性EZH 2 转基因小鼠模型。EZH 2转基因小鼠发生导管内上皮增生， 核BRCA 1蛋白下调和组织学特征再现人类疾病。基于 在这项工作中，我们竞争性更新的中心假设是，EZH 2过表达是由于EZH 2的过度表达导致的。 乳腺通过调节BRCA 1蛋白和功能诱导乳腺增生。我们进一步 假设在EZH 2过表达情况下额外的特异性致癌事件， 引发癌症的快速发展，从一开始就具有高度侵袭性。具体 目标是：目标1。研究EZH 2在转基因小鼠乳腺中是否过表达 使用乳腺肿瘤发生的良好表征模型加速肿瘤发展和转移 概括EZH 2过表达的人浸润性乳腺癌;目的2.确定 EZH 2调节BRCA 1蛋白和BRCA 1介导的肿瘤抑制功能的机制; 目标3：评价EZH 2单独或与BRCA 1（a）联合检测作为一种新的诊断方法的临床价值， 乳腺癌风险增加的组织生物标志物，和（B）作为能够鉴定哪些小的 浸润性癌具有高转移潜能。我们将研究EZH 2过表达对 使用由女性良性乳腺组织组成的独特资源， 随后发展为乳腺癌，以及一组乳腺浸润性癌， 1期和2期（< 2 cm），随访10年。这些研究将提供更好的诊断， 准确预测不良预后和开发新疗法的潜力。

ABSTRACT 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 overexpressed 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 upregulated 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 downregulation 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 overexpression 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 overexpression in the mammary gland of transgenic mice accelerates tumor development and metastasis using well-characterized models of breast tumorigenesis that recapitulate EZH2 overexpressing 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 overexpression 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.