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

描述（由申请人提供）：虽然一般来说，原发性肿瘤越大，其转移或已经转移的可能性越大，但这并不总是最常见的。 案子许多小乳腺癌发生转移，结果令人沮丧。表征驱动这些肿瘤快速进展的基因可以识别新的生物标志物，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。我们在上一个资助期的工作集中在基质细胞蛋白CCN 6在乳腺肿瘤发生中的作用，这是未知的。我们已经令人信服地证明，虽然CCN 6蛋白在乳腺上皮细胞中表达，但在60%的浸润性乳腺癌中减少或丢失，这与预后不良有关。我们已经清楚地表明，在体内和体外降低乳腺癌的侵袭和转移。我们的初步数据和目前的建议与该实验室的长期目标是一致的：了解与乳腺癌进展相关的基本机制，并将其转化为临床应用。我们已经证明，在非致瘤性乳腺细胞中CCN 6的下调破坏了正常的腺泡组织，并触发了上皮向间充质转化（EMT）和侵袭，这需要BMP 4介导的TAK 1和p38通路的激活，已知促进转移。我们的实验室提供了人类CCN 6和BMP 4信号之间的第一个机制联系。CCN 6与乳腺癌细胞中的BMP 4蛋白结合并减少侵袭。然而，这种相互作用对乳腺癌转移的机制细节和体内后果需要进一步研究。目前提案的总体目标是确定CCN 6减少乳腺癌转移的潜在机制，并将生物学发现转化为临床领域。核心假设是CCN 6抑制了 乳腺癌的进展通过结合BMP 4和拮抗BMP 4介导的TAK 1和p38激酶活化对EMT、侵袭、迁移和转移的作用。我们提出了以下三个假设驱动的具体目标。目标1：研究乳腺中CCN 6条件性敲除的体内结果，并确定参与乳腺癌进展的关键CCN 6蛋白基序。目的2：探讨CCN 6在体内抑制肿瘤转移的作用机制及其与BMP 4/TAK 1/p38信号通路的关系。目的3：确定CCN 6和BMP 4通路在人乳腺组织样本中的翻译影响。我们将研究CCN 6对EMT，侵袭和转移以及BMP 4/TAK/p38信号转导的影响。调控CCN 6的表达可能是预防和/或减少乳腺癌转移的重要药物靶点。今年全球有超过120万名女性被确诊，这些研究有可能提供更好的诊断、更准确的诊断，并为未来基于CCN 6的小分子药物的开发铺平道路。

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. 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.