Role of CCN6 (WISP3) in the progression and metastasis of breast cancer

摘要 乳腺癌是女性癌症死亡的第二大原因，也是最常见的癌症 在女性中。乳腺癌患者死亡的主要原因是 转移，一个仍然知之甚少的过程。表征调控生长的基因， 乳腺癌的转移能力可能会发现新的生物标志物，以帮助临床医生指导当前的 治疗，并可能提供新的治疗目标。我们已经鉴定了CCN 6 [WISP 3（Wnt-1诱导的 信号蛋白3）]在具有高转移性的乳腺癌组织样品中下调 能力CCN 6是CCN家族的一员，其介导上皮和上皮细胞之间的串扰。 基质和调节基本过程，包括细胞分化和生长。新出现的数据 表明CCN蛋白在癌症中失调。在我的K 08奖资助的研究中， 研究CCN 6在乳腺癌中的作用，这是未知的。我们发现CCN 6具有肿瘤 在体内和体外乳腺癌中的抑制功能。我们发现CCN 6干扰了 IGF-1及其信号通路在乳腺上皮细胞中的生长作用。最近，我们的实验室 进行了新的观察，在良性乳腺上皮细胞中抑制CCN 6会导致上皮细胞 向间质转化（EMT）转变，E-cadherin表达显著下调。我们的核心假设 CCN 6在乳腺癌的发病机制中起着因果作用。我们假设， 乳腺中的CCN 6通过以下方式促进肿瘤生长、侵袭和转移：（a）调节CCN 6的表达， IGF-1对乳腺上皮的生长作用，和（B）抑制E-钙粘蛋白复合物。 乳腺癌中CCN 6的丢失可能会导致一组侵袭性和转移性肿瘤。具体目标 目的1：探讨CCN 6在乳腺发育中的作用 目的2：探讨IGF-1信号通路与肿瘤细胞凋亡的关系，为进一步研究IGF-1信号通路在肿瘤细胞凋亡中的作用奠定基础。 CCN 6介导的上皮细胞向间充质细胞转化的生物学意义和分子基础 乳腺癌;目的3：确定CCN 6缺失是否加速乳腺肿瘤的生长 以及它们的转移潜能。我们将 研究CCN 6抑制对EMT过程和体内IGF-1信号传导的影响， 独特的人体组织资源，包括正常乳腺、导管原位癌 （DCIS）、浸润性癌以及淋巴结和远处转移。调控CCN 6的表达 可能是防治乳腺癌的重要药物靶点。这些研究 为更好地诊断、更准确地预测不良预后和开辟新的治疗途径提供了可能。 新疗法的潜力。项目叙述 乳腺癌是女性癌症死亡的第二大原因，也是女性中最常见的癌症。 妇女这项研究解决了妇女健康的一个重要方面，即CCN 6如何调节生长。 和上皮分化的乳腺肿瘤，并防止恶性转化。如果我们能阻止 或在转移性肿瘤中重新激活它，我们将大大改善乳腺癌的预后， 数百万妇女的生命。这些研究可能成为乳腺癌干预和治疗的基础， 潜在地防止癌前病变恶化和转移。

ABSTRACT Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in patients with breast cancer is the development of metastasis, a process that is still poorly understood. Characterizing genes that regulate the growth and metastatic ability of breast cancer may identify novel biomarkers to help clinicians guide current treatments, and may offer new targets for therapy. We have identified CCN6 [WISP3 (Wnt-1 induced signaling protein 3)] as being down-regulated in tissue samples of breast cancers with high metastatic ability. CCN6 is a member of the CCN family, which mediate cross-talk between the epithelium and the stroma and regulate fundamental processes including cellular differentiation and growth. Emerging data show that CCN proteins are deregulated in cancer. In studies funded by my K08 award, we have begun to study the role of CCN6 in breast cancer, which was unknown. We showed that CCN6 has tumor inhibitory functions in breast cancer in vivo and in vitro. We discovered that CCN6 interferes with the growth effects of IGF-1 and its signaling pathway in the mammary epithelium. Recently, our laboratory made the novel observation that inhibition of CCN6 in benign breast epithelial cells causes an epithelial to mesenchymal transition (EMT) with marked down regulation of E-cadherin. Our central hypothesis is that CCN6 plays a causal role in the pathogenesis of breast cancer. We postulate that loss of CCN6 in the breast promotes tumor growth, invasion and metastasis by (a) regulating the growth effects of IGF-1 on the mammary epithelium, and (b) repressing the E-cadherin complex. CCN6 loss in breast cancer may drive a group of aggressive and metastatic tumors. The specific aims of this project are as follows: Aim 1: To determine the role of CCN6 in regulating the growth of breast cancer in vitro and in vivo and its relationship with IGF-1 signaling pathways; Aim 2: To investigate the biologic implications and the molecular basis of CCN6 mediated epithelial to mesenchymal transition in breast cancer; Aim 3: To determine whether CCN6 loss accelerates the growth of mammary tumors and their metastatic potential using well-characterized mouse models of breast tumorigenesis. We will investigate the effect of CCN6 inhibition on the process of EMT and on IGF-1 signaling in vivo using unique human tissue resources consisting of samples of normal breast, ductal carcinoma in situ (DCIS), invasive carcinomas, and nodal and distant metastases. Regulating the expression of CCN6 may represent an important drug target for prevention and cure of breast cancer. These studies have the potential of providing better diagnosis, more accurate predicting of poor prognosis and open the potential for new therapies. PROJECT NARRATIVE 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 CCN6 regulates the growth and epithelial differentiation of breast tumors and prevents malignant conversion. If we could prevent the loss of CCN6 or reactivate it in metastasizing 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.