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，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 上一个资助期的工作集中在基质细胞蛋白CCN 6在乳腺癌中的作用， 肿瘤发生，这是未知的。我们已经令人信服地证明，虽然CCN 6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， 与不良结局相关。我们已经清楚地表明，减少乳腺癌的侵袭和转移， 体内和体外的癌症。我们的初步数据和目前的建议是符合长期的 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，在非致瘤性肿瘤中CCN 6的下调， 乳腺细胞破坏正常的腺泡组织并触发上皮细胞向间质细胞转化（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CCN 6和BMP 4信号传导之间的第一个机制联系， 人类CCN 6与乳腺癌细胞中的BMP 4蛋白结合并减少侵袭。但 这种相互作用对乳腺癌转移的机制细节和体内结果需要进一步研究。 调查本提案的总体目标是确定可能的机制， CCN 6减少乳腺癌转移，并将生物学发现转化为临床领域。中央 有一种假说认为CCN 6通过与BMP 4结合并拮抗BMP 4抑制乳腺癌进展。 BMP 4介导的TAK 1和p38激酶活化对EMT、侵袭、迁移和转移的影响。 我们提出了以下三个假设驱动的具体目标。目的1：研究在体条件下， 乳腺中CCN 6条件性敲除的后果，并确定关键的CCN 6蛋白 参与乳腺癌进展的基序。目的2：探讨CCN 6介导的细胞凋亡的机制。 体内转移抑制功能及其与BMP 4/TAK 1/p38信号传导的关系。目标3： 确定CCN 6和BMP 4途径在人类乳腺组织样本中的翻译影响。我们将 研究CCN 6对EMT、侵袭和转移的影响以及对BMP 4/TAK/p38信号传导的影响。 使用独特的人体组织资源。调节CCN 6的表达可能代表了一个重要的 用于预防和/或减少乳腺癌转移的药物靶标。有超过120万女性 这些研究有可能提供更好的诊断， 准确的计算，为今后基于CCN 6的小分子的发展铺平了道路。

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.