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

描述(申请人提供)：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。乳腺癌患者的主要死亡原因是转移，这一过程仍然知之甚少。确定调控乳腺癌生长和转移能力的基因可能会识别新的生物标志物，帮助临床医生指导当前的治疗，并可能为治疗提供新的靶点。我们已经发现CCN6[WISP3(WNT-1诱导信号蛋白3)]在高转移能力的乳腺癌组织样本中下调。CCN6是CCN家族中的一员，它介导上皮和间质之间的串扰，并调节包括细胞分化和生长在内的基本过程。新出现的数据显示，CCN蛋白在癌症中被解除调控。在我的K08奖资助的研究中，我们已经开始研究CCN6在乳腺癌中的作用，这是未知的。我们发现CCN6在体内和体外对乳腺癌具有抑瘤作用。我们发现CCN6干扰IGF-1的生长效应及其在乳腺上皮细胞中的信号通路。最近，我们的实验室进行了一项新的观察，发现良性乳腺上皮细胞中CCN6的抑制导致了上皮向间充质转化(EMT)，并显著下调了E-钙粘附素的表达。我们的中心假设是CCN6在乳腺癌的发病机制中起因果作用。我们推测，CCN6在乳腺中的缺失通过(A)调节IGF-1对乳腺上皮的生长作用，以及(B)抑制E-钙粘素复合体，从而促进肿瘤的生长、侵袭和转移。CCN6在乳腺癌中的缺失可能导致一组侵袭性和转移性肿瘤的发生。本项目的具体目标如下：目的1：确定CCN6在体内外调控乳腺癌生长中的作用及其与IGF-1信号通路的关系；目的2：探讨CCN6介导的乳腺癌细胞上皮向间充质转化的生物学意义和分子基础；目的3：利用已建立的乳腺肿瘤形成的小鼠模型，确定CCN6缺失是否加速了乳腺肿瘤的生长及其转移潜能。我们将利用独特的人类组织资源来研究CCN6抑制对EMT过程和体内IGF-1信号的影响，这些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的样本。调控CCN6的表达可能是防治乳腺癌的重要药物靶点。这些研究有可能提供更好的诊断，更准确地预测不良预后，并打开新疗法的潜力。公共卫生相关性：乳腺癌是女性癌症死亡的第二大原因，也是女性最常见的癌症。这项研究解决了女性健康的一个重要方面，即CCN6如何调节乳腺肿瘤的生长和上皮分化，并防止恶性转化。如果我们能防止CCN6的丢失或在转移的肿瘤中重新激活它，我们将极大地改善乳腺癌的预后，拯救数百万女性的生命。这些研究可能形成乳腺癌干预和治疗的基础，潜在地防止癌前病变变得恶性和转移。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.