Role of CCN6 (WISP3) in the Progression and Metastasis of Breast Cancer.

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，情况并不总是这样。许多小乳腺癌发展为转移和 有一个令人沮丧的结果。表征驱动这些肿瘤快速发展的基因可能会识别出 帮助临床医生指导当前治疗的新生物标记物，并可能提供新的治疗靶点。我们的 在之前的资助期间，工作重点是基质细胞蛋白CCN6在乳房中的作用 肿瘤的发生，这是未知的。我们已经令人信服地证明，虽然CCN6蛋白是 在乳腺上皮细胞中表达，在60%的浸润性乳腺癌中减少或丢失， 与糟糕的结果相关。我们已经清楚地表明，它可以减少乳房的侵袭和转移 体内和体外的癌症。我们的初步数据和目前的建议与长期 本实验室的目标：了解乳腺癌进展的基本机制 并将其转化为临床应用。我们已经证明CCN6在非致瘤性疾病中的下调 乳腺细胞破坏正常的腺泡组织并触发上皮向间充质转化(EMT) 侵袭性，这需要BMP4介导的TAK1和p38通路的激活，已知促进 转移。我们的实验室已经在CCN6和BMP4信号之间提供了第一个机制联系 人类。CCN6与乳腺癌细胞中的BMP4蛋白结合，降低侵袭力。然而， 这种相互作用对乳腺癌转移的机制细节和体内后果还需要进一步研究 调查。本提案的总体目标是确定潜在的机制， CCN6可减少乳腺癌转移，并将生物学发现转化为临床领域。中环 假设CCN6通过与BMP4结合并拮抗BMP4而抑制乳腺癌的进展 BMP4介导的TAK1和p38激酶激活在EMT、侵袭、迁移和转移中的作用。 我们提出了以下三个假设驱动的具体目标。目的1：体内研究 乳腺CCN6条件性基因敲除的后果及关键CCN6蛋白的确定 与乳腺癌进展有关的基序。目的2：探讨CCN6介导的细胞毒作用机制 肿瘤转移抑制基因在体内的作用及其与BMP4/TAK1/p38信号转导的关系目标3：实现 确定CCN6和BMP4途径在人类乳腺组织样本中的翻译影响。我们会 探讨CCN6对人卵巢癌细胞EMT、侵袭转移及BMP4/TAK/p38信号转导的影响 活体利用独特的人体组织资源。调控CCN6的表达可能代表着一个重要的 预防和/或减少乳腺癌转移的药物靶点。有120多万名女性 今年在全球范围内确诊，这些研究有可能提供更好的诊断，更多 准确的预测，为基于CCN6的小分子的未来发展铺平了道路。

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. Our work in the prior funding period focused on the role of the matricellular protein CCN6 in breast tumorigenesis, which was unknown. We have convincingly demonstrated that while CCN6 protein is expressed in breast epithelial cells, it is reduced or lost in 60% of invasive breast carcinomas, where it is associated with poor outcome. We have clearly shown that decreases invasion and metastasis in breast cancer in vivo and in vitro. Our preliminary data and the current proposal are consistent with the long-term objectives of this laboratory: to understand basic mechanisms associated with breast cancer progression and translate them into clinical utility. We have shown that downregulation of CCN6 in nontumorigenic breast cells disrupts normal acinar organization and triggers an epithelial to mesenchymal transition (EMT) and invasion, which requires BMP4-mediated activation of TAK1 and p38 pathway, known to promote metastasis. Our laboratory has provided the first mechanistic link between CCN6 and BMP4 signaling in humans. CCN6 binds to BMP4 protein in breast cancer cells and reduces invasion. However, the mechanistic details and in vivo consequences of this interaction to breast cancer metastasis need further investigation. The overall goal of the current proposal is to determine the potential mechanisms whereby CCN6 reduces breast cancer metastasis and to translate biologic findings into the clinical field. The central hypothesis is that CCN6 suppresses breast cancer progression by binding to BMP4 and antagonizing the effect of BMP4-mediated activation of TAK1 and p38 kinases on EMT, invasion, migration, and metastasis. We propose the following three hypothesis-driven specific aims. AIM 1: To investigate the in vivo consequences of CCN6 conditional knockout in the mammary gland and to define the critical CCN6 protein motifs involved in breast cancer progression. AIM 2: To determine the mechanism of CCN6-mediated metastasis suppressor function in vivo and its relationship to BMP4/TAK1/p38 signaling. AIM 3: To ascertain the translational impact of CCN6 and the BMP4 pathway in human breast tissue samples. We will investigate the effect of CCN6 on the EMT, invasion and metastasis and on BMP4/TAK/p38 signaling in vivo using unique human tissue resources. Regulating the expression of CCN6 may represent an important drug target for prevention and/or reduction of breast cancer metastasis. With more than 1.2 million women diagnosed this year worldwide, these studies have the potential of providing better diagnosis, more accurate prognostication, and pave the way for future development of small molecules based on CCN6.